ES2350973T3 - DISGREGATION SYSTEM OF A FORMULATION OF POWDER AND DRY POWDER INHALERS. - Google Patents

Abstract

A disintegration means for dry powder inhalers, comprising a substantially cylindrical air circulation chamber (3), being a height smaller than its diameter, the chamber having a cylindrical wall and at least two supply channels (2, 9) of air entering the chamber (3) as tangents to the cylindrical wall (5) on generally opposite sides of this wall (5), suitable for creating a circular air flow model within the chamber (3) or having the two different air channels (2, 9) or alternatively sharing the same inlet that divides, so that it has a step (2) to go through the dose measurement region or the inhaler dose supply to allow the amount of powder from a single dose is drawn into the air circulation chamber (3) that flows through this step (2) and to serve the other step as a bypass channel (9) to the appropriate circulation chamber (3) to accelerate the split and creating a more symmetrical flow model within said chamber (3), characterized in that the number of bypass channels (9) is between one and eight, preferably three, the channels being preferably substantially symmetrically distributed along the circumference of the wall (5, 10) of the circulation chamber (3) [in addition to the channel (2) that crosses the middle of the inhaler dose] and the shape of the circulation chamber (3) has corners, preferably has eight corners, having the chamber wall (5) (3) sides of different lengths, in which the longer sides (32) and the adjacent smaller sides (22) alternate, serving the longer sides (32) as sides of acceleration along with speed of gain of motion particles to increase the speed of impact, the smaller sides being suitable as impact sites.

Description

Technical Field of the Invention

The field of the invention relates to dry powder inhalers for the supply of a medicament or a mixture of medicaments, to the respiratory tract. Dry powder inhalers are designed to store and provide a powder formulation, which contains the drug in the correct particle size for deposition in the lungs, intense, effective, comprising a dosing system for reproducible administration of the amount of powder required to the patient, a disintegration system to release drug particles from the powder formulation and a mouthpiece. Background of the invention Dry powder inhalers

It is a historical tradition to divide dry powder inhalers into (a) single dose, (b) multiple unit dose and (c) multidose devices. For inhalers of the first type, the manufacturer has weighed single-dose in small containers, which are mostly hard gelatin capsules. A capsule should be taken from a separate box or container and inserted into an area of the inhaler receptacle. Next, the capsule must be opened or pierced with needles or sharp blades in order to let part of the inspired air stream pass through the capsule to drag the powder or discharge the powder from the capsule through these perforations by means of Centrifugal force during inhalation. After inhalation, the empty capsule must be removed from the inhaler again. Normally, it is necessary to disassemble the inhaler to insert and remove the capsule, which is an operation that can be difficult and cumbersome for some patients. Other drawbacks related to the use of hard gelatin capsules for inhalation powders are: (a) poor protection against moisture absorption from ambient air, (b) problems with opening or perforation after the capsules have previously been exposed to extreme relative humidity, which causes fragmentation or cutting and (c) possible inhalation of capsule fragments. On the other hand, for a series of capsule inhalers, incomplete expulsion has been indicated (for example, Nielsen et al., 1997).

Some capsule inhalers have a chamber from which individual capsules can be transferred to a receiving chamber, in which perforation and emptying takes place, as described in WO 92/03175. Other capsule inhalers have rotating chambers with capsule chambers that can be aligned with the air duct for dose discharge (for example, German patent DE 3927170. They comprise the type of multi-dose inhalers together with blister inhalers, that have a limited number of single-dose units on a disc or a strip for supply. Blister inhalers provide the medication with better moisture protection than capsule inhalers. Access to dust is obtained by perforating the cover as well as the blade from the blister or peeling off the cover sheet.When using a blister strip instead of a disc, the number of doses can be increased, but the inconvenience for the patient is to replace the empty strip.Therefore, such devices are frequently disposable with the built-in dose system, including the technique used to transport the strip and open the blister cavities beef.

Multi-dose inhalers do not contain previously dosed amounts of the powder formulation. They consist of a relatively large container and a dose measurement principle that can be operated by the patient. The package contains multiple doses that are individually isolated from the entire powder by volumetric displacement. There are various principles of dose measurement, including rotary membranes (for example, European patent EP0069715) or discs (for example, French patent FR 2447725; European patent EP 0424790; German patent DE 4239402 and US patent. 5829434), rotary cylinders (for example, European patent EP 0166294; British patent GB 2165159 and international patent WO 92/09322) and rotary logs (for example, US patent 5437270), all having cavities that have to be filled with powder from the container. Other multi-dose devices have measuring plates (e.g., U.S. Patent 2587215; U.S. Patent 5113855 and U.S. Patent 5840279) or measuring plungers with a local or circumferential recess to displace a certain volume of powder from the container to a supply chamber or an air duct, for example, European patent EP 0505321, German patent DE 4027391 and international patent WO 92/04928.

Reproducible dose measurement is one of the main concerns for multi-dose inhaler devices. The powder formulation has to have good and stable flow properties, since the filling of the dosing cups or cavities is mainly influenced by the force of gravity. The patient has to handle the inhaler correctly and especially to keep the device in the correct position while operating the dose measurement principle. Only a few examples of special means for facilitating the filling of the powder are known, for example, European patent EP 0424790 (vibratory means) and the international patent WO 92/04928 (collar type portion for guiding the dust into the hole in a plunger) . To pre-charge single dose and multi-dose inhalers, the manufacturer can guarantee the accuracy and reproducibility of the dose measurement. On the other hand, multi-dose inhalers may contain a much larger number of doses, while the number of manipulations to prepare a dose is generally lower.

Because the air flow inspired by multidose devices is often in a straight line due to the dose measurement cavity and because the dose measurement systems of multidose inhalers, which are solid and rigid, cannot being agitated by the inspired air stream, the powder mass during the discharge is simply dragged from the cavity and almost no deagglomeration occurs. Therefore, separate means of disintegration are necessary. However, in practice, they are not always part of the design of the inhaler. Due to the high number of doses in multidose devices, the adhesion of the powder to the inner walls of the air ducts and the means of deagglomeration should be minimized and / or regular cleaning of these parts should be possible, without affecting the doses residuals in the device. Some multi-dose inhalers have packaging for disposable drugs that can be replaced after the prescribed number of doses has been taken (for example, U.S. Patent 5840279). For such semi-permanent multi-dose inhalers with disposable drug containers, the requirements to prevent drug accumulation are even more stringent. Powder formulations

Many size ranges have been proposed as optimal for inhalation drugs, including 1-5 µm (international patent WO 95/11666), 0.1-5 µm (international patent WO 97/03649), 0.5-7 µm ( Davies et al., 1976) and 2-7 µm (Kirk, 1986). Particles larger than 7 µm are deposited mainly in the oropharynx by inertial impact; Most particles between 0.1 and 1 micrometer are exhaled again as a result of their low deposition efficiency in the entire airways (Martonen and Katz, 1993). Different techniques are available for the production of said small particles, for example, micronization of larger crystals with a jet mill or other comminution equipment, precipitation of (super) saturated solution, spray drying or supercritical fluid methods. Products obtained with different techniques may differ in their surface properties and therefore, in cohesiveness and / or adhesiveness. The degree of particle-to-particle interaction has an influence on the process of deagglomeration during inhalation.

The very cohesive nature of micronized particles and the low amounts in which inhalation drugs are administered to obtain the desired therapeutic effects, generally between 10 and 400 µg, with an exception for prophylactic drugs (eg, disodium cromoglycate) and antibiotics (for example, colistin sulfate) (both in the mg range), makes it very difficult to achieve the reproducibility necessary in administration to the patient. Therefore, it is necessary to make the drug or the association of drugs in a suitable powder formulation. Currently, two different types of powder formulation for inhalers are widely used: spherical granules and adhesive mixtures. Adhesive mixtures are also referred to as ordered mixtures (Hersey, 1975) or interactive mixtures (Egermann, 1983). A special type of adhesive mixtures are core agglomerates, also referred to as supersaturated ordered mixtures (Schmidt and Benke, 1985) or core agglomerates (international patent PCT / EP95 / 02392).

In spherical granules, micronized drug particles, with or without micronized excipient (lactose), have subsequently agglomerated and spheronized to form larger, spherical and thus loose granules. The size range of said granules is approximately 100 to 2,000 µm. No binders have been used, but the amount of absorption water may have been controlled to increase cohesiveness. In general, the granules for inhalation are very weak and have very low densities between 0.28 and 0.38 g / cm3 (NL C1008019, 1999).

Adhesive mixtures consist of relatively large crystals, generally alpha-lactose monohydrate, that carry micronized drug particles on their surface. Classic mixing techniques can be used to obtain the desired degree of homogeneity. Good homogeneity and adequate flow properties are not the only prerequisites for good dose reproducibility. However, during inhalation, the drug particles have to be separated from the carrier crystals before they can enter the lower respiratory tract. It has been recognized that the surface properties of the carrier play an important role in the drug-to-carrier interaction and thus, in the extent of separation during inhalation.

There are several reasons why either of the two types of powder formulations may be incompatible with a certain inhaler design. Due to their high sensitivity to impact forces, spherical granules should not be used preferably in inhalers with a volumetric powder container together with a measuring principle that the patient has to operate for the isolation of a single dose. If the patient drops the inhaler, the loose granules can be deformed into a mass of dust without form that cannot be loaded into the volumetric dose measuring cavities in a reproducible manner. Adhesive mixtures with low drug concentrations on the other hand, should preferably not be used in conjunction with previously loaded dose compartments with a volume much larger than the powder. Drug particles can be transferred from the carrier crystals to the inner walls of the compartment in an extension of more than 30% of the drug dose. This can result in high losses of the dose of fine particles emitted, because the particles that can be easily transferred from the carrier particles to the compartment walls are also the particles from which better removal forces can be achieved during inhalation Carrier materials in adhesive mixtures

In adhesive mixtures for inhalation, the most widely used as a carrier excipient is crystalline alpha-lactose monohydrate. The size distribution of the carrier fraction may vary with the specific demands regarding dust flow, drug loading, emptying of the dose compartment, fine particle detachment during inhalation and physiological effects from carrier deposition in the airways, etc. Bell et al. (1971) found a better discharge from perforated hard gelatin capsules in the Fisons Spinhaler for a fraction of 70-100 µm BP-lactose. Silvasti et al.

(1996) described that the lactose size fraction used for the Orion Easyhaler is large enough to avoid deposition of the material in the lower parts of the airways, without specifying the exact range of sizes. Podczeck (1998) referred more specifically to thick carrier particles in the size range between 50 and 200 µm, which are physiologically inert. Almost the same fractions of 30 to 80 µm, respectively 30 to 90 µm, are mentioned in US Pat. 5478578 and by Timsina et al. (1,994). In international patent WO 95/11666 it is claimed that the carrier particles are advantageously between 50 and 1,000 µm, preferably less than 355 µm (26 to 250 µm) and even more preferably between 90 and 250 µm to have better flow properties.

The use of granular carrier materials has also been described. International patent application WO 87/05213 describes a 'conglomerate', which consists of a water soluble vehicle (for example, lactose) or a mixture of such vehicles and a suitable lubricant (for example, magnesium stearate) in a range sizes between 30 and 150 µm as new carrier excipients for inhalation powders. European patent EP 0876814 A1 describes roller-dried beta-lactose in a size fraction of 50 to 250 µm (preferably 100-160 µm) as an excipient suitable for inhalation of dry powder. This type of lactose has a granular appearance and a roughness between 1.9 and 2.4 is particularly recommended. In the same patent, crystalline �-lactose monohydrate (with a roughness of 1.75) and spray-dried lactose (with a roughness between 2.4 and 2.8) are rejected as lower carriers for inhalation drugs.

The effect of carrier surface properties has been studied in more detail by Podczeck (1996) and Kawashima et al. (1,998). Podczeck used ten different marketed products of alpha-lactose monohydrate to prepare adhesive mixtures with salmeterol xinafoate. The results of the study show that the relationship between the physical properties of the lactose-bearing particles and the depositor data of the impactor is complex and that a simple exchange of carrier material for another brand or grade is impossible. It was concluded that the crystalline alpha-lactose products supplied by DMV International and Borculo Whey Products (both from the Netherlands) show a surface roughness that decreases when the particle size decreases, while the Meggle products (Germany) show an opposite correlation . Kawashima et al. they prepared mixtures of hydrated pranlukast with similar fractions of size of types and completely different modifications of lactose and found that the dose supplied from the Spinhaler (at 60 I / min) increases with increasing the specific surface area of the carrier fraction, while decreasing the fine particle dose. They concluded that the absolute surface roughness of the carrier crystals does not seem to be important, but rather the roughness scale (microscopic versus macroscopic). For granules with the so-called 'superparticle' roughness, the interparticulate junctions between drug and carrier are high as a result of interlocking. International patent WO 95/11666 describes that it is often found that the roughness and cracks in the surface of a carrier particle are an area of high surface energy whereby the active particles have a preference to deposit and adhere as strongly as possible. . Buckton (1,997)

explains significant differences in the physical carrier surface properties by differences in both surface energies and solid state properties, such as the presence of amorphous material in the carrier crystals.

The treatment of the carrier crystals prior to mixing with the drug for the improvement of its properties as a carrier material has been described in the international patent WO 95/11666, the international patent WO 96/23485 and the international patent WO 97/03649. The treatment in the international patent WO 95/11666 consists in the careful grinding of the carrier particles, preferably in a ball mill for several hours at a low rotational speed. During treatment, the roughnesses such as small grains detach from the surface of the carrier and bind to high-energy sites in cracks, while the size of the carrier particles remains substantially unchanged. International patent WO 96/23485 describes the addition of small amounts of anti-stick or anti-friction material, such as magnesium stearate, leucine or silicon dioxide, as fine particles to the carrier crystals for the occupation of active sites. .

An increase in the fraction of fine particles released from adhesive mixtures during inhalation has also been achieved by adding fine excipient particles (lactose) to these mixtures. Zeng et al. (1998) found that the addition of 1.5% intermediate lactose (DMM = 15.9 µm) to an adhesive mixture with salbutamol sulfate and carrier fraction of 63-90 µm increases the fraction of fine drug particles of the Rotahaler in the double collider (60 l / min) with more than 60%, compared to the mixture without the fine lactose fraction. An additional 9% (w / w) increase in the finest lactose in the mixtures increased the fraction of fine drug particles with another 50%. U.S. Pat. 5478578 claims that the inhalable portion of the active substance in inhalation powders can be controlled within wide limits, while maintaining good measurement accuracy, by combining the micronized active substance with adequate amounts of a mixture of acceptable excipients. One component of the excipient mixtures has to have an average particle size of less than 10 µm, while the other component has to have an average diameter greater than 20 µm (generally below 150 µm and preferably below 80 µm ).

Forces of particle-to-particle interaction and breaking forces

Proper disaggregation of dust during inhalation occurs when the separation forces exceed the interaction forces between the particles. Separation forces can be generated in different ways and include in devices currently marketed for example: (a) inertial forces in the impact of particles with each other or against the walls of the inhaler, (b) frictional forces

or shear that act in agglomerates that are detached by a wall of the inhaler and (c) dispersion forces in turbulent air currents, such as dragging and lifting forces. In dry powder inhalers powered by breathing, the separation forces generally become greater as the inspiratory effort increases as a result of the increased air velocity. The effectiveness by which available energy can be dissipated in rupture or detachment depends on many other factors as well, such as the type of formulation (granules or adhesive mixture) that is subjected to these forces, the order of magnitude for interparticulate forces in the formulation and the direction in which the removal forces act on the dust agglomerates, more particularly on drug particles bonded to the carrier surfaces. Because the orientation of the particles on impact cannot be controlled, repeated collision may be necessary to obtain the correct direction for the detachment of said particles.

Previously, it has been described that the surface properties of lactose carrier crystals can have a spectacular effect on the interaction between drug and carrier particles in adhesive mixtures. They can also have an effect on removal forces. The drag and lift forces are rather ineffective for the release of small drug particles from larger carrier crystals. This is especially the case, when the surface of the carrier crystals is not smooth (as for granules) and fine particles can be stored away in surface discontinuities. For carrier particles with greater surface roughnesses, friction forces cannot break adhered drug particles, simply because these fine particles do not make contact with the walls of the inhaler along which the carrier particles vibrate, roll or they slide. Inertial forces on the other hand, such as impact deceleration forces, can be highly effective in the direction of the original movement of the particles before the collision. The timing of fine particles and thus the efficiency of removal in this direction increases not only with the increase in air velocity but also with greater mass for the adhering particle, which can also be a small agglomerate of fine particles . Therefore, incomplete rupture of fine drug particles during mixing seems to be an advantage for this type of removal force.

Deceleration forces can only be effective in the release of drug particles, when there is a free path for these particles to move away from the carrier crystal. When the wall of the inhaler with which the carrier particle collides is clogged, the drug particles in the middle of the carrier and this wall of the inhaler can become even stronger bound to the surface of the carrier as before the collision. The same is true for particles attached to the opposite surface of the carrier or particles obstructed by projections on the carrier surfaces perpendicular to the wall of the inhaler struck, although to a lesser extent, due to the increase in the binding force to these surfaces of Carrier depends on the moment of fine particles and not on the much larger carrier moment. An increase in ligation strength should be expected when the contact area between a drug particle and the carrier crystal can be increased under load. This may be, for example, the result of the existence of ductile surface layers of lactose impurities. For the principles of disaggregation that have inertial forces, the surface discontinuities of the carrier can be an advantage, since (a) they can provide a free path for separate fine particles and (b) they can store agglomerates of larger fine particles that remain intact for the mixing process and have a much greater momentum, which is transferred to a force of removal on impact, than the primary drug entities. Because the detachment of drug particles from carrier crystals takes place only in one direction and part of the adhered drug particles can become even stronger in impact, repeated collision at relatively high speed is necessary to obtain a Acceptable fine particle fraction of adhesive mixtures during inhalation.

The energy required for the rupture of soft spherical granules on impact depends greatly on the structure of these granules (Coury and Aguiar,

1995 and Boerefijn et al. 1,998). Many different theoretical proposals have been presented to predict the resistance of the granules and compacts, starting with Rumpf (1,962) and Cheng (1,968). In most of these proposals, the tensile strength of the granules is expressed as a function of the average interaction force per contact point, the size of the primary particles in the granule and the average coordination number. The assumption made for these theoretical proposals applies quite well for micronized inhalation drugs, which generally consist of more or less spherical particles that do not vary extremely in size. On the other hand, the interaction forces between the particles are all of the same order of magnitude and the rupture of the granules is through the binding sites between the particles.

Additional improvements can be made to the theoretical proposals in terms of interaction force per unit of contact area and total contact area between two particles. The coordination number can be expressed in the porosity of the powder, which is extremely high for soft spherical inhalation granules. Corresponding to an indicated density (�P) of approx. 0.30 to 0.40 g / cm3 (NL C1008019, 1999), the porosity values (� = 1-�S / �0) can be between 0.69 and 0.77 (for a true particle density, �0, 1.3 g / cm3). The interaction forces between particles in inhalation granules are generally of the van der Waals type.

Recent work has shown that defects in the granules can cause the nucleation of cracks through which the rupture takes place (Coury and Aguiar, 1995). Such defects reduce the energy required for breakage considerably. Extremely porous soft spherical granules for inhalation have a high degree of discontinuity, representing many defects from which disintegration can begin. Boerefijn et al. (1998) demonstrated that the disintegration of soft spherical lactose granules for inhalation is measured with the square of the impact velocity. They also investigated the effect of storage conditions and granule size on the type and extent of the fracture. In contrast to solid materials, they found that smaller granules have a much greater extent of rupture than larger agglomerates (for granules stored in a desiccator at a relative humidity of 5%). They also observed that granules exposed to a relative humidity of 87% are much more resistant to breakage than dry granules, due to a change in interparticle forces. Fractional losses of dry impacted granules (between 5 and 30 percent by mass) consist mainly of single particles and only smaller groups of primary particles. Samples exposed to 87% RH have much smaller fractional losses on impact (mass percentage between zero and twelve), which consist of small scales well below the size of the original granule. It was found that the nuclei of the dried granules deformed much more as a result of the internal shear than the wet agglomerates, presenting rather a semi-fragile mode of rupture.

Similarly to adhesive mixtures, the different types of separation forces are quite different in their efficiencies for breaking soft spherical granules. Drag forces (for example, in turbulent flow regions) are not as effective when the granules are already suspended in the air. But when the granules are forced into a dose compartment and air flow is suddenly conducted through this compartment at high speed, the dust can be broken to a large extent and rise from the compartment rather as smaller fragments than in volume . The drag forces are effective in particular in breaking said dust when the air flow can pass through the highly porous dust mass itself rather than through large interparticular pores; that is, when the granules have been joined in a lump of dust. For this principle, a very high rate of increase of the flow towards the maximum flow is necessary. But it can also be achieved by the sudden expansion of air inside a mass of dust, for example, by creating a sub-or overpressure in the pore volume of the powder in a closed dose compartment in relation to the pressure in an adjacent spacer first and connecting the dose compartment quite suddenly with the very large spacer volume next.

The frictional forces are very effective for the deagglomeration of soft spherical granules, as has been shown for the Astra Turbuhaler (for example, Steckel and Müller, 1997; de Boer et al., 1997 and Koning, 2001). The majority of the granule dose can be broken into much smaller entities during a relatively small passage through an air duct with a helical insert, providing fine particle fractions in vitro between 40 and 60% of the labeled claim. During contact between the granule and the walls of the inhaler, the frictional forces and also the attractive forces of van der Waals are imposed directly and exclusively on the primary particles along the periphery of the granule that separates them from the mother granule as primary entities or as small groups. A disadvantage of this principle is that van der Waals forces and possibly also the chiropractic forces make these smaller entities adhere to the wall of the inhaler to a considerable extent. The accumulations of the inhaler from 15 to 25% of the dose are quite normal.

Inertial forces are also, however, the most effective for spherical granules. Due to their highly porous and rather anisotropic structure, the granules can be deformed quite easily on impact. This deformation causes internal shear and rupture, resulting in the separation of the fragments, as observed by Boerefijn et al. (1,998). When the granules are circulating with high speed in an aerosilization chamber for a certain duration of time, repeated collision between particles and the chamber wall or particle collision with each other can be performed, so that fragment disintegration is completed Separated bigger.

Because different types of separation forces may have different efficiencies for the same type of formulation, there are unfavorable combinations for the powder formulation and the principle of disaggregation. As previously discussed, the drag and shear forces in turbulent air currents are very ineffective with respect to the release of fine drug particles from carrier crystals in adhesive mixtures. Incomplete disintegration for this type of formulation can also be achieved in air ducts with helical inserts. For spherical granules on the other hand, a good deagglomeration can be obtained in said air channels, as well as in circulation chambers in which repeated collision between particles or particles and the inhaler wall takes place. But intensive particle-to-wall contact should not result in substantial dose losses by adhesion of the particles on this wall. Optimization with respect to (a) degree of granule fracture and (b) accumulation of fine particles is necessary.

Incompatibilities have the implication that powdered formulations cannot be exchanged at will for a given type of disaggregation principle, since inappropriate disintegration or significant loss of adhesion drug particles may result. This reduces the versatility of an inhaler concept considerably. Dust deagglomeration in dry powder inhalers

In many dry powder inhalers controlled by breathing, the powder deagglomeration is linked to the emptying of the dosing system. All or part of the air flow of the inspiration, respectively auxiliary, is directed to, by or past the dose compartment in which a single dose has been weighed to empty the compartment and transport the dispersed powder to the airways, such as It is described for example in British patent GB 1118341, German patent DE 3016127, US Pat. 4811731, U.S. Pat. 5113855, U.S. Pat. 5840279 and the international patent WO 92/09322.

The air flow can be turbulent or have special flow models to disperse the dust by means of shear and drag forces or by particle-to-particle collisions (for example, Hovione report of ref. DY002-rev. 4, 1995) or the Air flow can cause the dose container to initiate a certain movement (rotation or vibration) by which dose discharge and disaggregation is stimulated. These are mechanisms used in particular for capsule inhalers, as described for example in US Pat. 3507277; U.S. Patent 3669113; U.S. Patent 3635219; U.S. Patent 3991761; French patent FR 2352556; U.S. Patent 4353365 and U.S. Pat. 4889144. A major disadvantage of capsule inhalers is that the movement of rotation, oscillation or vibration of the capsules during inhalation causes intensive contact between the powder and the inner walls of the capsule and the friction and shearing of the powder at Along these walls frequently result in substantial accumulation of drug. In contrast to the capsules, the blister packs cannot easily be subjected to vibration or rotation movement.

It has been recognized that simply conducting (part of) the air flow inspired by or past the dose compartment does not provide the desired degree of rupture for dust agglomerates. Different solutions have been proposed for the improvement of dust dispersion, varying from the introduction of (a) narrow air passages, such as venturi tubes, to increase local air velocities, (b) tilbes, plates or walls, of impact placed in such a way in the air stream that they impact large, inert agglomerates, against them, (c) air channels in which the air is forced to take a tortuous path, for example, by means of helical inserts and (d ) special circulation chambers in which particles circulate and impact each other or against the walls of the chamber.

Examples of narrow air passages for the stream of charged air of particles have been described in US Pat. 2587215, French patent FR 2447725, German patent DE 4027391 and international patent WO 93/09832. More specifically, narrow channels of the venturi type are known from, for example, US Pat. 4046146, British patent GB 2165159, US Pat. 5161524 and U.S. Pat. 5437270. Disagglomeration means of this type may have quite high air flow resistance and the total surface area of the inhaler walls that is in contact with the micronized drug particles is quite large, which is a disadvantage from the point of view. of adhesion of fine particles in these walls. On the other hand, high local air velocities, in a venturi throat, can facilitate the entrainment of dust from the dose cavity in this region by suction (Bemouilli effect), but it is not likely that the high velocity of Extreme turbulence results that facilitate the breakdown of dust, because the venturi tubes are basically designed to minimize turbulent flow.

Inhalers that use impact walls or tilbes also include devices with curved sections of the mouthpiece. The obstructions in the air duct cause the flow of air laden with particles to change their direction. The larger particles with much greater inertia than the air, are unable to follow the tortuous path and impact the obstructions, which is supposed to result in the breakdown of the agglomerates. The use of tilbes in an extension for the inhaler is described in the international patent WO 92/05825, while the impact deagglomeration of the particles on the internal surfaces of the mouthpiece is claimed for example by Parry-Billings et al. (2,000) for the Clickhaler multi-dose inhaler.

Inhaler devices, in which the air flow inspired by particle agglomerates through nozzle channels with insert bodies or special internal profiles takes place, are numerous. Frequently, the insert bodies have a helical shape, forcing the air stream to follow a spiral path. The particles in the air stream are subjected to a centrifugal force and tend to concentrate outside the helical passage. In this outer peripheral region, the more or less spherical type of agglomerate granule rolls along the cylindrical wall of the discharge channel. The friction and shear forces involved cause the primary particles or small groups to separate from the outer shell of the granules. The much more irregular carrier particles in adhesive mixtures vibrate, rather than roll, through the wall of the channels and repeated collisions can lead to detachment of adhered drug particles. Examples of nozzle channels helical insert bodies are given for example in US Pat. 4907538, European patent EP 0424790 and European patent EP 0592601. An inhaler with a so-called striated chimney, with a hexagonal cross-section, is described in US Pat. 5829434. The particles, which enter the chimney in a spiral path movement, collide repeatedly with the internal walls of the chimney, thus transferring their kinetic energy to the shedding of fine particles or rupturing of agglomerates.

The principles of deagglomeration that consist of special circulation chambers, in which the particles circulate and impact each other or against the walls of the chamber will be described in more detail from now on.

The degree of powder deagglomeration in dry powder inhalers controlled by respiration by all the above-mentioned principles of disintegration is determined by the inspiratory effort of the patient, that is, the performance of the inhaler depends on the inhalation maneuver. If the effort does not meet the requirements for a particular inhaler design, the drag and fine particle generation may be incomplete. Therefore, the deposition of the drug in the target area may be insufficient to obtain the desired therapeutic effect. Even with maximum effort, the maximum pressure drop by a dry powder inhaler is limited to approx. 2 to 20 kPa, while the maximum total volume to be inhaled is between 1 and 3 liters, both depending on the clinical picture and the patient's age and more particularly the resistance of the inhaler to air flow.

It has been recognized that it is practically impossible to design a principle of deagglomeration that of a consistent degree of powder deagglomeration over a wide range of flow rates, when this principle derives its energy only from the inspired air stream (International Patent WO 94/23772). The underlying reason for this is that higher inspiratory air flows tend to lead to higher air velocities inside the inhaler and thus, greater impact or shear forces and greater turbulence. At greater effort, more energy is simply available to break up particle agglomerates.

Several proposals have been presented to reduce or eliminate the variability in the fine particle intake of dry powder inhalers controlled by respiration as a result of a variation in inspiratory flow curves. For example, the application of valves has been proposed, the patient has first achieved the opening after a threshold flow for a good disintegration (for example, US Patent 5301666). U.S. Pat. 5161524 describes a maximum speed regulator, placed within a secondary air flow channel. More complex solutions are described in international patent WO 94/23772 for an inhaler with a compensatory breaker geometry for changes in air flow and German patent DE 4237568 for the generation of a subpressure in a dispersion chamber.

Dose discharge and powder deagglomeration dependent on inspirational effort can also be eliminated using pressurized air or mechanically generated sub-pressures. On the other hand, much larger pressure differences can be applied by the powder dispersion system (> 100 kPa, equal to 1 bar, for overpressures). The aerosol can be discharged from the dose system into a space chamber before it is inhaled and the inhalation can be at relatively low flow rates, thus reducing deposition in the throat. An average flow rate (�) of 30 l / min is quite reasonable for a breath-controlled inhaler with a moderate air flow resistance (R) of 0.04 kPa0.5.min.l-1. From this, an average pressure drop (dP) during inhalation of 1.44 kPa (1.44 x 103 Nm-2) can be calculated, using the simplified equation for a type of flow constriction orifice: � dP = R.�. It is also reasonable for this resistance of the inhaler, a total inhaled volume (V) of 1.5 liters (1.5 x 10-3 m3), corresponding to the total energy (E = V.dP) of 2.16 Nm that It is available for powder dispersion. Spacers have relatively small volumes to keep the dimensions of the inhaler within acceptable limits. But even for a spacer with a volume of only 250 ml, an average pressure drop of no more than 8.64 kPa (�0.09 bar) would be necessary to generate the same energy and thus, the same degree of dust rupture by the same principle of disintegration. The designs and efficiencies (in the use of available energy) of the principles of disintegration may however be different. Examples of dry powder inhalers that apply pressurized air systems for powder deagglomeration are described in German patent DE 2435186, US Pat. 3906950, U.S. Pat. 5113855, German patent DE 4027391 and international patent WO 9962495.

Other ways of applying auxiliary energy for the discharge of the dose compartment and powder deagglomeration is (a) by means of electrically driven impellers, as described, for example, in US Pat. 3948264, U.S. Pat. 3971377, U.S. Pat. 4147166 and the international patent WO 98/03217 or (b) with a battery-operated piston, drug particles derived from a tape (international patent WO 90/13327). Auxiliary energy systems are often bulky and sensitive to substantial adhesion of fine drug particles to their large internal walls or have a complex design and structure and are vulnerable with respect to battery failure.

A special group of dry powder inhalers that are more or less independent of the patient's inspiratory effort with respect to the accuracy of the dose emission and fine particle output is constituted by the drag systems. European patent EP 0407028, German patent DE 4027390 and international patent WO 93/24165 describe principles of cutting, dragging or erosion that remove small amounts of dust from a drug compact by rotational movement of the abrasive sheets against the compact by a default rotation angle. European patent EP 0407028 describes the combination of such a principle with a cyclone chamber to select only the finest particles for inhalation and more evenly spread the bolus of the entrained powder, so that the dose of medication is inhaled for a longer period of time. long. The dragging principles share the problem of micronized powder tablet formation, which has to provide a completely isotropic compact, maintaining a constant hardness under different environmental conditions. It is quite problematic to obtain the distribution of desired drug sizes for inhalation by drag separation of portions of said compact. Prior art

Most of the principles of disaggregation described previously have a great disadvantage in common: the discharge of the dose from the inhalation device takes place rather momentarily. The residence time of the powder in the deagglomeration means is extremely short, in relation to the total period during which the air is extracted by the inhaler device. Therefore, the efficiency in the use of the available energy is quite low and most of the air is used only for transporting the drug particles generated in the respiratory tract. As a result, the disaggregation of the powder, especially that of adhesive mixtures, is often very incomplete and the amount of drug particles released in the desired size range is quite low (20% to 40% of the nominal dose). Accordingly, an optimal therapeutic effect of one dose is not obtained. In addition, all particles are discharged from the inhaler regardless of their size. For some drugs, this may be undesirable due to significant adverse side effects of deposition in the mouth and throat. For example, it has been indicated that corticosteroids initiate hoarseness and Candidiasis after deposition in the throat (Selroos et al., 1994).

The principles of disaggregation that consist of special circulation chambers, from which particles can be discharged more gradually into the respiratory tract, can reduce these disadvantages. Generally, circular flow models inside such chambers are created by the construction of one or more tangential inlet channels that terminate in the cylindrical wall of the disc-shaped chamber (or tube-shaped). The residence time of the dust inside the chamber can be influenced by the balance of the drag force and the centrifugal force and in the extreme situation in which the centrifugal force is dominant, the tangential flow provides the possibility of retaining particles more large by centrifugal separation. The invention described in this patent application is of the circulation chamber type of deagglomeration principle. It is a modular concept with different modifications, each of these modifications having quite different characteristics. The principles of disaggregation described previously that are particularly important for this invention are either those of the same type (circulation chamber) or those of a different type but that share one or more of the same characteristics, including (a) control of the residence time, (b) retention of large particles and (c) control of airflow resistance, as will be explained in more detail from now on.

Inhalers with internal circulation chambers have been described, for example, in British patent GB 1478138, French patent FR 2447725, German patent DE 4004904, European patent EP 0407028, international patent WO 91/13646, international patent WO 92/04928, European patent EP 0547429, German patent DE 4239402, German patent DE 19522416 and international patent WO 01/60341 A1 (Art.54 (3) EPC). A very recent concept of a tangential flow chamber is described in British patent GB 1118341. This patent describes an open cup (for example, capsule) for the dose of powder that is placed on a vertical support rod in the center of a hollow chamber An air jet, which enters through a hole in the lid on the chamber, goes to the cup to discharge the dust. Supplementary air currents, which enter through the radial inlet holes in the cylindrical wall of the chamber at the same level as the open end of the dust cup, are forced to a tangential route by special air barriers or spiral inversions . Turbulence in the circular air stream is expected to help the dispersion of the dust in the air stream.

A basically similar concept is described in British patent GB 1478138. The inhaler consists of a cylindrical container with a nozzle tube, with the same longitudinal axis but a smaller diameter than the container. The connection between both parts is through a narrow tubular extension of the nozzle tube, which protrudes into the container. It is also the outlet of the nozzle by a narrow tube, which protrudes in the nozzle cylinder. Air enters the device through two series of openings, which create a whirl movement inside the container as well as in the nozzle cylinder. The dust, which is put inside the container, is carried in the current of air that circulates. The centrifugal force causes the heavier particles to be thrown out against the walls of the container, while the finer particles will be removed by the narrow tubes in the airways by the action of the drag force.

A completely different design for a circulation chamber is described in German patent DE 4004904 A1. A discharge channel divides the flow of air laden with particles into a main stream and a secondary stream; the last one entering a cyclone circulation chamber (disk shape). In the region in which the air flow is divided, the main stream is directed upwards by a 90 degree curve in the air duct, when the inhaler is held in the correct position during inhalation. In the vertically directed step downstream of the curve, the drag force is opposite to the force of gravity. This causes larger agglomerates to fall to the bottom of the channel, while only fine particles can be dragged further into the mouthpiece of the inhaler. The deposited agglomerates are joined at the site where the secondary current returns to the main current after a 180 degree rotation has been made in the cylindrical chamber. The turbulence in this region disintegrates the agglomerates until they become small enough to be transported by the drag force of the main stream to the mouthpiece of the inhaler.

The circulation chamber described in European patent EP 0407028 A2 is referred to as a particular arrangement of air passages or cyclone means, within which entrained drug particles can circulate. Particle-laden air enters the chamber through a single air inlet that is tangential to its cylindrical wall. A venturi tube adjacent to the junction of the inlet channel with the cyclone chamber accelerates the air flow in this chamber. The discharge of the chamber is through an exit channel along the longitudinal axis of the chamber. The claimed advantages of the arrangement are that (a) only the finest particles in a population of particles of various sizes are selected for inhalation, while

(b) the boluses of the entrained dust spread more evenly, so that the dose of medication is inhaled for a longer period of time. The cyclone chamber is described together with a consolidated drug supply and a scraping sheet as a means of measuring the dose. Comparable circulation or swirl chambers of different designs with a tangential inlet channel are presented in the international patent WO 90/15635. The concepts differ in the position of the exit channel and in the diameter and shape of the vortex chamber, being either a tube, a disc or a disc with a funnel-shaped section towards the exit channel, with the same axis longitudinal than the whirl chamber.

A disk-shaped cavity with two specially shaped, opposite inlet channels, which provides a turbulent stream of air inside the cavity, is mentioned in French patent FR 2447725. In the patent, it is described that the disaggregation does not have place in the cavity, but rather in a region of the helical insert inside the central suction tube of the inhaler, also being the outlet channel of the cavity. For the commercialized concept of this invention, the Pulvonal high strength dry powder inhaler described by Meakin et al. (1998), the cavity is referred to as an aerosolization chamber. It is now claimed that the deagglomeration takes place in a narrow passage between the centrally raised bottom of this aerosolization chamber and the suction tube above that.

International patent WO 92/04928 refers to a so-called spiral mixing chamber that has the shape of a disk with a rounded cylindrical wall. Suction takes place through tangential air channels that enter the chamber through holes in its rounded wall. Inside the vortex mixing chamber, a first air flow is guided through the dust compartment and a second air flow collides with the first air flow in substantially transverse direction. This is to mix the air and dust in a desired way. In another example, the powder is discharged into the chamber from an offset extruder type dosing mechanism.

European patent EP 0547429 A1, German patent DE 19522416 A1 and international patent WO 01/60341 A1 (Art. 54 (3) EPC) describe different concepts, each for a different application, of basically the same type of camera circulation. In the basic principle described in European patent EP 0547429 A1, the flow of dust-laden air from the dose compartment is mixed with a flow of air without particles before the mixture of the two flows enters a cyclone chamber by specially shaped slits in a central tube protruding from the bottom of the cyclone in the chamber. The slits create a tangential flow model inside this chamber, which has a cylindrical shape with truncated cones at the top and bottom of the cylinder. The mixing of the partial air flows is to increase the velocity of the particles inside the cyclone chamber, thereby increasing the deagglomeration forces, in particular those for adhesive mixtures. The discharge of fine drug particles detached is through a special channel that is co-axial with the cylindrical axis of the cyclone chamber and partly protrudes from this chamber. The discharge channel widens towards the patient's mouth to reduce the velocity of the particles at the entrance to the airways and avoid the prolonged action of the cyclone inside this channel. Another part of the inspiratory air flow is used to create a co-axial wrap flow without particles around the aerosol cloud of fine drug particles. The central inlet duct for inspiratory air may have a special valve, which opens first after the patient generates sufficient pressure drop to ensure good dose dragging and dust deagglomeration. In an alternative design, the circulation chamber has a rounded bottom, while the tangential air currents are from the cylindrical wall of the chamber.

International patent WO 01/60341 A1 (Art. 54 (3) EPC) describes an application of this basic type of disaggregation principle for a colistin sulfate formulation. Because the high powder load of the high dose of colistin in CF treatment can be a burden on the patient, the concept has been specially modified to retain larger excipient crystals in the inertial separation formulation. Accordingly, the deposition of dust in the respiratory tract can be limited to the active ingredient only. The excipient particles in the formulation for this type of disaggregation principle do not act as a carrier or as a diluent, but as a cleaner, removing the adhered fines of the active substance from the internal surface of the disintegration chamber. The formulation may be a physical mixture in which there is no appreciable interaction between the cleaner crystals and the drug particles, as in adhesive mixtures. This has the advantage that the surface properties of the carrier are irrelevant to the fraction of fine particles obtained during inhalation.

The specific design described in the international patent WO 01/60341 A1 (Art. 54 (3) EPC) is not applicable for the type of spherical granule of formulation without cleaning crystals, due to the strong adhesion of the fine particles to the internal walls of the circulation chamber. For this application, a third concept has been developed, as described in German patent DE 19522416 A1. The concept has the same cylindrical chamber as the basic concept in European patent EP 0547429 A1, but the mixing of particle-laden flow (dust flow) with a particle-free air flow is now inside the chamber instead of in the air channel to this chamber. In the example shown, the number of so-called bypass channels for the additional air flow is seven, but there may be more, as well as fewer channels. In addition, there is an eighth tangential slit for dust flow. The discharge of the deagglomeration chamber is through a channel that begins at the center of the cylindrical end of the disc-shaped chamber, with the same longitudinal axis as this chamber. In the modification described in German patent DE 19522416, the discharge channel does not protrude to the deagglomeration chamber. This discharge channel has a minimum length and a strongly reduced diameter to minimize losses of fine particles by adhesion to its internal walls. The concept in German patent DE 19522416 can also be used for adhesive mixtures, although the efficiency of deagglomeration is somewhat less than that of the concept described in international patent WO 01/60341 A1 (Art. 54 (3) EPC).

Unlike the concept in the international patent WO 01/60341 A1 (Art. 54

(3) EPC), there is no retention of large particles. Large particles are discharged from the deagglomeration chamber gradually with a speed that is determined by the dimensions of the chamber and the size distribution of the carrier. A certain period of residence is considered within the principle of disaggregation as an advantage, as previously discussed and will be explained in more detail from now on. The time required for total discharge should not exceed the total inhalation time. Recent guidelines prescribe that the total drug dose be inhaled within 2 liters, which corresponds to an inhalation time of 2 seconds at an average flow rate of 60 l / min.

The type of disaggregation principle described in European patent EP 0547429 A1, German patent DE 19522416 A1 and international patent WO 01/60341 A1 (Art. 54 (3) EPC), has a particle-free envelope flow that can reduce the deposition of fine particles in the patient's mouth of return flows. The envelope flow is particularly effective for spherical granules, because the emitted aerosol cloud generated from this type of formulation does not contain large agglomerates with high inertia that can migrate through the thin envelope of clean air under the influence of centrifugal forces in The spiral path discharge flow model. For adhesive mixtures, the importance of the envelope flow is mainly limited to maintaining the resistance to the airflow of the inhaler within acceptable limits.

German patent DE 4239402 A1 describes a complex combination of a residence chamber with a distribution chamber and a disintegration chamber for inhalation dusts that can either consist of spherical granules or be an adhesive mixture. The residence chamber is a disc-shaped part of the air passage between the dose measurement system and the nozzle outlet. Its longitudinal axis is perpendicular to the longitudinal axis of the nozzle cylinder. The air laden with particles passes through an acceleration channel, which ends at the periphery of the residence chamber and is discharged tangentially into this chamber. The air outlet channel of the residence chamber is at a cylindrical end, co-axial with the cylindrical axis of the residence chamber. It ends in an adjacent distribution chamber that is also disk-shaped and has the same longitudinal axis as the residence chamber. Connected to the distribution chamber is a tangential output channel, referred to as a disintegration chamber. The acceleration channel towards the residence chamber, the outlet channel of the distribution chamber and the nozzle cylinder have parallel longitudinal axes. It is claimed that the discharge of the dust from the residence chamber is quite gradual and that the majority of the dose is not yet released before the patient has achieved the maximum flow rate. As for the principle described previously, prolonged residence maximizes the use of dispersion forces. Further disaggregation takes place in the disintegration chamber in which the flow of dust from the intermediate distribution chamber is accelerated. At the end of the patient, the disintegration channel widens to decrease the velocity of air and particles. This reduces the deposition of the mouth and throat.

All previously mentioned circulation chambers are incorporated in a particular inhaler design. On the contrary, the international patent WO 98/26827 refers to a principle of powder deagglomeration and particle classification that is in fact an extension of the mouthpiece of a dry powder inhaler. The patent application refers to developments of earliest dry powder inhalers in which cyclone chambers have been used for (a) the purpose of effecting deagglomeration and / or (b) separating heavier and lighter particles from each other in a air / dust mixture. The authors reject such use of cyclones, because the effectiveness in any of the aforementioned applications is determined by the suction power that a patient is able to apply to the mouthpiece. For the invention described in the international patent WO 98/26827, the primary function of a cyclone chamber is neither to effect deagglomeration nor to separate particles by size, but to retain in orbit the heavier particles that have previously separated from the particles. lighter by a 'circulatory section' upstream of the cyclone chamber. In a given example, this circulatory section is a frusto-conical body that fits a lot in a funnel-shaped box. The flow conduit is in the form of one or more helical shaping steps along the sharp circumference of the frusto-conical body, between this body and the funnel-shaped box. The conversion of axial to helical flow is quite steep against the upper part of the frusto-conical body. The particles are breaking down on the impact against this surface. It is claimed that the finest and largest particles are largely separated in the helical passages by centrifugal action, the finer particles following a spiral path with a smaller radius than the larger particles.

Downstream of the circulatory section of this invention, air is conducted from the passages near the inner wall of the funnel-shaped box toward the central axis of this box along the bottom of the trunk. In this region of flow, where the drag force is opposite to the centrifugal force, more classification takes place. Only fine particles are then discharged through the outlet duct that is co-axial with the trunk axis by a narrow passage in a funnel-shaped lid on the box. Large particles continue to circulate during inhalation in a cyclone chamber adjacent to the circulatory section or accumulate at the base of this chamber, but fine particles released during this circulation are not discharged into the airways because there is no flow from it. camera to the tracks.

Another special application of a circulation chamber is presented for the Asmanex Twisthaler (Momethasone Furoate) (US Patent 5740792, US Patent 5829434 and Fan et al., 2,000). The Twisthaler sprayer includes to break up the dust agglomerates: (a) cavity means, (b) swirl means and (c) chimney means. The cavity means and the swirl means constitute a chamber called swirl (Fan et al., 2,000). Particles carried from the dose measuring cavity through (part of) the inspiratory air travel through the inhalation channel into the swirl chamber. This swirl chamber is basically a cylindrical hollow chamber with an internal wall (swirl media) that crosses this chamber in an arched path. The wall is to divert the air stream charged with particles in a tangential route. The swirl imparted is maintained when the air passes through the chimney. As a result, dust agglomerates that are carried through the air, with a much greater inertia than the air, constantly impact the internal walls of the swirl chamber and the swirl wall that conducts the air through this chamber (US Pat. U.S. 5829434). The agglomerates also collide with each other, which results in an action of grinding or mutual breaking between them. It is described that the particles are accelerated at a critical rate for rupture inside the swirl chamber by the addition of secondary air flow in this chamber (Fan et al., 2,000 and US Patent 5829434). Unlike the patent (US patent 5829434), Fan et al. They explain that dust collisions on the wall in the chimney are the key mechanism of rupture in the formation of fine particles for inhalation. For a better realization of this breaking of fine particles in the chimney, the inner walls of this part of the deagglomeration means have been provided with grooved edges (for example to provide a hexagonal cross-section).

Some of the concepts described previously present specific disadvantages or limited applications. One of the possible consequences of the application of a circulation chamber is the increased resistance to the total airflow of the inhaler, as described for example by Meakin et al. (1998) for Pulvonal dry powder inhaler. Especially for concepts with more than one camera, as described in German patent DE 4239402, the increase must be substantial. Although high resistance is not unconditionally a disadvantage (for example Svartengren et a., 1995), patients with reduced lung power should be able to generate sufficient air flow for proper device realization. This is required regardless of the design of the principle of deagglomeration, unless a constant external energy source is used for dose dragging and powder deagglomeration. The prior separation of the particles in a circular section of the flow duct upstream of the cyclone chamber, as described in international patent WO 98/26827, does not reduce or eliminate this problem, because the detachment of fine particles of the carrier crystals still depends on the size of the separation forces in this section.

A major concern is the adhesion of fine particles in the internal walls of circulation types of deagglomeration media, as described in the international patent WO 01/60341 A1 (Art. 54 (3) EPC). The total area of parts of the inhaler that are in contact with fine drug particles is often quite large, as for German patent DE 4239402, international patent WO 98/26827 and US Pat. 5829434. At regular time intervals, the disaggregation means of this type must be disassembled for inspection and / or cleaning, which does not always seem possible (for example, German patent DE 4004904). Disassembly should be simple and may not be inconvenient for the patient. In addition, reassembly after inspection and / or cleaning may not lead to inhaler malfunction. One of the consequences of adhesion of fine particles is that most ips (dry powder inhalers) with a circulation chamber as a means of disintegration are not suitable for spherical granules. For adhesive mixtures, the problem is less extreme, because larger carrier particles can clean most of the fine adhering of the walls of the inhaler.

Although some of the previously reviewed patents refer to a certain residence of the dust inside the deagglomeration means (for example, the German patent DE 4004904, the European patent EP 0407028, the German patent DE 4239402 and the German patent DE 19522416 ), the possibility of controlling residence time is not mentioned for any of the principles. Only the possibility of varying the residence time has been described in German patent DE 19522416, by changing the ratio of the velocities of the partial air flows by, respectively around the circulation chamber and by modifying certain dimensions of the chamber, such as height and diameter.

Some of the previously mentioned patents refer specifically to the retention of coarse particles, for example, British patent GB 1478138, European patent EP 0407028, international patent WO 92/05825, international patent WO 92/04928, European patent EP 0547429, the international patent WO 98/26827 and the international patent WO 01/60341 A1 (Art. 54 (3) EPC). The particles with high inertia that are thrown out by the whirling movement of air into the container described in British patent GB 1478138, circulate through the inner wall of this container. They cannot pass through the narrow tubular extension of the nozzle cylinder that protrudes from the container along the same longitudinal axis of this container. A second thick particle trap is a narrow tubular passage at the outlet of the nozzle cylinder. The cyclone media described in European patent EP 0407028 A2, European patent EP 0547429, international patent WO 98/26827 and international patent WO 01/60341 A1 (Art. 54

(3) EPC) operate on the basis of the same principle of two competitive forces, which are the centrifugal force and the drag force. But the concept in the international patent WO 92/04928 is basically different, although the separation is also in the inertia of the particles. A separate suction piece is described downstream of the swirl chamber, in which large particles with high momentum follow a straight path in a dead-end tube, while the finer particles are dragged by the air stream to a tube. secondary. The separated coarse particles are collected at the bottom of the tube with no outlet (collection chamber), which must be emptied from time to time. The inertial impact is also the separation mechanism for impact jets with different tilbes and plates described in the international patent WO 92/05825.

Some of the separation principles mentioned above on the basis of centrifugal dragging are described as cyclone means. This is incorrect, because they are not designed to separate all solid material from the air stream, but to classify airborne particles into two kinds of sizes based on their inertia, which means that they are basically classifiers of air, as referred to in British patent GB 1478138. However, none of the patents have mentioned the limit diameters of the classifiers, except for the international patent WO 92/05825, which provides formulas with experimental constants for the different types of impact jets. This patent application also explains that the limit diameter can be adjusted to suit a particular drug and a particular application.

Only two concepts are known by which the resistance to air flow can be controlled within certain limits. In US Pat. 5829434 it is described that the pressure drop by the swirl nozzle can be changed by varying the cross section for air flow in the passage between the swirl chamber and the chimney. It is indicated that the pressure drop by the inhaler should be desirably less than about 5 kPa for ease of use by patients with reduced respiratory function. For the beginning in the German patent DE 19522416, it is explained that the inspiring air stream can be divided into a partial flow through the disintegration chamber and a partial flow past this chamber to create an envelope flow without particles around the cloud of emitted spray. The relationship of these flows can be varied within certain limits without influencing the drag of the dose and the disintegration of the powder.

Summary of the invention

The invention is defined in claims 1 and 14.

The present invention provides a multiple disperser for inhalation powders, which can be used together with different types of dose systems for the dose weight range between 2 and 25 mg and different types of powder formulation (with or without carrier excipients) . In a particular design, the disperser acts both as a means of deagglomeration (disintegration; aerosolization) and as an air classifier for especially adhesive mixtures. Only fine drug particles are emitted while larger agglomerates and carrier crystals are retained by the disperser. The modification of the basic design allows the controlled release in time of carrier crystals in these mixtures. In another modification, the concept presents optimized embodiment as a disperser together with spherical granules, which do not contain carrier crystals. It is possible to further redesign the dispersion principle to control the total resistance of the inhaler and the deposition of dust in the upper respiratory tract by adding a so-called clean air envelope flow. The modifications also allow for the retention of bearer at the nozzle and the elimination of the tangential flow component of the discharge cloud. Description of the invention

The concepts described in European patent EP 0547429, German patent DE 19522416 and international patent WO 01/60341 A1 (Art. 54 (3) EPC) comprise a family of disaggregation principles for different applications, all of which are different modifications thereof basic design For all concepts, part of the inspiratory air flow is conducted through the dose compartment to drag dust. The downstream section of the dust channel, which connects the dose compartment and the deagglomeration chamber, is tangential to the cylindrical wall of the deagglomeration chamber. The deagglomeration chamber has the shape of a disk, which shares its cylindrical axis with the nozzle cylinder. A tubular discharge channel, also with the same longitudinal axis and a diameter much smaller than the deagglomeration chamber, starts from the center of the cylindrical end of this chamber that is closer to the nozzle. Another part of the inspiratory air flow enters the deagglomeration chamber through tangential slits in its cylindrical wall. The number of these bypass channels can be limited to only one, as for the concept described in the international patent WO 01/60341 A1 (Art. 54 (3) EPC) or there may be more, as in the German patent DE 19522416, depending on the specific application of the deagglomeration chamber. The partial bypass air flow increases the tangential velocity of the air and particles inside the chamber. A third of the inspiratory air flow is not conducted through the deagglomeration chamber but is diverted into an annular opening, which is co-axial with the discharge channel of the deagglomeration chamber. The air flow from this annular opening is co-axial with the air flow charged with particles from the deagglomeration chamber, thereby constituting an air shell with no particles around the aerosol.

The particles that circulate inside the deagglomeration chamber are subjected to three different forces: the air drag force, a centrifugal force and the force of gravity. The force of gravity is not relevant to the trajectories of airborne particles inside the chamber. The particles are thrown into the cylindrical wall of the deagglomeration chamber whenever the centrifugal force dominates. If they roll smoothly through this wall or vibrate with only brief moments of contact between the particle and the wall, it depends on many factors, such as the charge of the deagglomeration chamber, the number of bypass channels and the shape of the particles . Also important is the distribution of particle sizes in terms of this. If the particles are relatively large, the number of particles inside the deagglomeration chamber for a certain dose weight is small and the number of particle-to-particle collisions is limited. In addition, the loading of the chamber with particles can be quite asymmetric, depending on the weight of the dose and the discharge model of the dust channel. If on the other hand, the particles are relatively small, the number of particles inside the chamber is much larger and so will be the number of collisions between the particles, while the load can be much more homogeneous, since a large number of particles more evenly.

The difference between the concepts described in the German patent DE 19522416 and the international patent WO 01/60341 A1 (Art. 54 (3) EPC) is mainly its optimization for a specific application; The concept described in European patent EP 0547429 is the original design without optimization as an integral part of a multi-dose inhaler for which the individual doses in cavities on rotating discs have been weighed. The concept in German patent DE 19522416 has been optimized for the deagglomeration of soft spherical granules, but this concept serves very well for adhesive mixtures as well. The concept described in international patent WO 01/60341 A1 (Art. 54 (3) EPC) has been designed for adhesive mixtures in applications for which carrier retention is desired. The reasons for carrier retention may be different. Possible adverse side effects from substantial drug deposition in the patient's throat have already been mentioned. The carrier particles released are deposited in the throat as a result of their great inertia, even lower flow rates, when they are discharged from the inhaler and still carry drug particles on their surface at release. By removing the carrier particles from the inspired air stream, throat deposition can be greatly reduced. But also for formulation studies with adhesive mixtures, carrier removal can be valuable. The residual drug content can be analyzed in the retained carrier particles, in order to obtain information on the drug-to-carrier interaction and release of the drug during inhalation. This information is more accurate and reliable than that of fine particle fractions collected in an impactor, which are influenced by irreproducible adhesion losses on the inner walls of the inhaler, inlet tube and stages of the impactor and incomplete collection by the final stage.

The breaking mechanisms for the two types of formulations are basically different for the two concepts of disaggregation in German patent DE 19522416 and international patent WO 01/60341 A1 (Art. 54 (3) EPC). As the soft spherical granules roll along the cylindrical wall of a deagglomeration chamber, they are mainly supported by friction. The detached fine particles or small groups of primary particles either adhere to the wall of the chamber by van der Waals (or Culómbicas) forces or are carried by the flow of air into the discharge channel. Due to this adhesion of fine particles on the cylindrical wall in particular of the principle of deagglomeration, the concept described in European patent EP 0547429 cannot be used for soft spherical granules without the addition of so-called (large) cleaning crystals to the formulation, such as It is described in the international patent WO 01/60341 A1 (Art. 54 (3) EPC). Without these cleaning crystals, the spherical granule deagglomeration is (almost) complete after a certain time of residence in the deagglomeration chamber, but the reduction of the dose of fine particles emitted as a result of adhesion on the walls of the inhaler is by 50% or even more, depending on the type of drug to be inhaled.

In the concept described in German patent DE 19522416, the number of bypass channels has been increased to seven to reduce the surface of the cylindrical wall by a large number of interruptions and to create a circulation model within the chamber that forces that the granules collide with the remaining sections of the cylindrical wall at angles that are more obtuse than the angle between two neighboring sections of this wall. Instead of rolling down a wall of the continuous cylindrical chamber, the granules are constantly traversed by the 'air barrier' between the granules and the remaining sections. Rather, they pass almost by touching these sections and as a result of the strongly reduced contact area, the adhesion of fine particles on the cylindrical wall is minimized. The disaggregation is mainly due to shear of derivation flows. As the granules approach the next section of the wall of the cylindrical chamber, they enter the region where a bypass flow intersects its path at an angle of 45 degrees. As a result of the high air velocity through the bypass channels, which is approximately 10 m / s at a flow rate of 60 l / min by the inhaler, the relatively weak granules are broken into smaller fragments and eventually broken into primary particles or small groups, which are thin enough to be dragged into the discharge channel.

By contrast, the carrier particles in adhesive mixtures circulating in the concept described in the international patent WO 01/60341 A1 (Art. 54 (3) EPC), bounce against the cylindrical wall after collision with it as a result of its shape irregular, which prevents them from rolling smoothly like spherical granules. The trajectory can best be described as a route along neighboring parabolas, all of which are in the same plane that is perpendicular to the cylindrical axis of the deagglomeration chamber, with its upper parts directed to the center of this chamber. After bouncing against the wall, the particles are forced back towards the periphery of the deagglomeration chamber by the action of the centrifugal force, to find a next collision. Meanwhile the particles travel in a tangential direction through the chamber. On impact, fine drug particles detach from the carrier crystals, depending on the angle and speed of the collision with the wall. In the basic concept described in European patent EP 0547429 and international patent WO 01/60341 A1 (Art. 54 (3) EPC), there are only two interruptions in the cylindrical wall of the deagglomeration chamber. As a consequence, there is little disorder of the particle trajectories and the particles above the boundary diameter at a given inspiratory flow rate are retained quite fairly effectively. The upper parts of the parabolas are only a small distance from the cylindrical wall of the chamber, because the angle of collision is quite obtuse. Therefore, a certain distance is maintained between the bouncing particles and the discharge channel is maintained, even when the particles are at the top of a parabola. The extension of the discharge channel into the deagglomeration chamber contributes to the almost complete removal of large particles by reducing the cross section of the passage between the circulation chamber and the discharge channel. In this basic modification, the circulation chamber acts both as a means of deagglomeration and as an air classifier. Figure 1 shows the effectiveness of carrier removal of an air classifier concept similar to the concept described in international patent WO 01/60341 A1 (Art. 54 (3) EPC) for different narrow fractions of alpha-lactose size crystalline monohydrate at a low flow rate of 30, respectively 40 l / min. Only for fractions with a median diameter less than 50 µm, the efficiency is less than 90%. The nominal limit diameters for colistin sulfate (for a sample with a size distribution between 0.7 and 87 µm) in the same classifier, as derived from laser diffraction measurement of the aerosol cloud using a special inhaler adapter, as shown in figure 2. As the flow rate increases, not only does the average limit diameter decrease, but also the extent between individual inhalations.

The interruptions in the cylindrical wall of the deagglomeration chamber, the many bypass flows that intersect the trajectories of the particles as well as the elimination of the extension of the discharge tube protruding in the deagglomeration chamber in the concept of the German patent DE 19522416, influence the rebound trajectories of the carrier. The angles of impact are slightly sharper, the flow pattern within the deagglomeration chamber is more turbulent and the cross section of the passage between the circulation chamber and the discharge channel increases. As a result, the carrier particles can enter the discharge channel and a gradual emptying of the circulation chamber is obtained. As can be expected, the average residence time of the carrier increases as the flow rate increases for a certain fraction of the carrier size, due to the increase in centrifugal forces, which keep the particles in circulation. But the dependence on the flow decreases as the average carrier size increases; for carrier particles with an average mass diameter above 150 µm, the flow effect is subordinate within the range between 30 and 90 l / min. The residence time decreases as the average diameter of the carrier increases, because the variation in the rebound trajectories of the particles becomes greater with the increasing inertia of the particles and the deviation of the shape. Larger lactose carrier particles tend to have a much more irregular shape than thinner crystals, even if they are of the same batch of lactose and the corrective effect of the drag force exerted by the tangential flow of air into the chamber Circulation decreases with increasing inertia of the particles. As a consequence of the gradual release of carrier particles, the average residence time of these particles in the concept of German patent DE 19522416 is generally less than the total inhalation time. And as a result, the release of fine particles for the same adhesive mixture is less complete than the degree of removal obtained with the concept according to the international patent WO 01/60341 A1 (Art. 54 (3) EPC), with the benefit of almost complete carrier withdrawal.

Most characteristic for the invention is (a) division of the inspiring air stream into three different partial flows and (b) the presence of a disk-shaped circulation chamber, whose combination provides the possibilities for:

-create a wrap of air without particles around the aerosol cloud to reduce deposition in the mouth of spherical granules,

-control the resistance of the inhaler within a range that is comfortable for the patient and favorable with respect to drug deposition in the upper respiratory tract,

-create an air barrier inside the deagglomeration chamber that decreases the adhesion of fine particles on the inner walls of this chamber in case of deagglomeration of spherical granules,

- impose a certain residence time on large carrier crystals in the deagglomeration chamber to improve the utilization of the available energy for the detachment of fine particles, classifying the particles in a fraction of sizes that is favorable for deposition in the respiratory tract lower (which must be released) and a fraction that is too thick to enter the site of action (which must be retained) and

- deposition of large particles in front of the patient's mouth instead of in the throat, by the tangential component of the flow in the discharge cloud of the inhaler, as a consequence of which the large particles are immediately thrown laterally after leaving the mouthpiece . This allows the patient to rinse his mouth after inhalation and avoid the systemic or local side effects of this part of the dose.

Two more aspects of the invention are the desired duration of residence of the bearer in the disaggregation means and the possibility of controlling the residence time in the disaggregation chamber accordingly.

For the control of residence time, another concept has been developed with improved deagglomeration efficiency for adhesive mixtures, as will now be described as another new aspect of the invention. A more described aspect from now on, is the modular construction of the deagglomeration means that allows the exchange of different concepts within the same dry powder inhaler, depends on the type of formulation to be used and / or special requirements, such as a specific resistance to air flow for a particular group of patients or complete carrier retention. In several aspects it is provided:

A disintegration means for dry powder inhalers, comprising a substantially cylindrical air circulation chamber being a height smaller than its diameter and at least two air supply channels entering the chamber as tangents to its cylindrical side wall generally opposite of this wall, suitable for creating a model of circular air flow within the chamber, the two air channels or have different entrances or alternatively share the same inlet that is divided, so that it has a step to cross the region of Measuring the dose or dose supply of the inhaler to allow the amount of dust from a single dose to be drawn into the circulation chamber by air flowing through this step and the other step serves as a bypass channel into the circulation chamber suitable for accelerating the particles and creating a more symmetrical flow model within said chamber; a disintegration means for dry powder inhalers comprising a tubular discharge channel with approximately the same longitudinal axis as the circulation chamber but a much smaller diameter and an extension of this channel that protrudes in said chamber by a length that is less than the total height of the circulation chamber; a disintegration means for dry powder inhalers comprising a third air passage in addition to the two air supply channels previously mentioned for the circulation chamber,

or with a separate inlet channel or as a branch of the cyclone bypass channel, whereby the air flow, which is part of the total inspiratory flow, is controllable by means of a constriction of the air flow and whose passage ends in an annular opening between the discharge channel of the circulation chamber and a co-axial nozzle cylinder with internal diameter greater than the discharge channel, to control the total airflow resistance of the inhaler device and to create a wrap of clean air around the aerosol cloud that reduces deposition in the mouth of drug particles released from spherical granules that is a consequence of the return flows that take place in the mouth during inhalation by an inhaler with a nozzle cylinder tubular typically having a diameter smaller than the height or width of the mouth cavity; a disintegration means for dry powder inhalers comprising more than one, preferably seven, air supply channels for the bypass flow, all of which are substantially symmetrically distributed along the circumference of the cylindrical wall of the circulation chamber, in addition to the channel which crosses a compartment of the dose of the inhaler, when used, providing a so-called air barrier between the circulating particles and the inner wall of the chamber created by air flows through the bypass channels that are closely adjacent to each other, as well as a reduced surface of said wall, further providing very small fine particle adhesion on said wall, especially for association with soft spherical granules; a disintegration means for dry powder inhalers, in which obtuse angles of approximately 135 degrees are provided between the remaining sections of the cylindrical wall by the air supply channels entering the circulation chamber, which when used provides a increase of the angle of impact and causes the particles to bounce against these sections of the chamber wall towards the center of this chamber by a greater distance that allows the carrier particles to approach or cross the central area of the circulation chamber from which can enter the discharge channel, which results in a gradual release of carrier particles from the circulation chamber through said discharge channel; a disintegration means for dry powder inhalers in which an upper end of the circulation chamber on its side of the discharge channel forms an upper plate of said chamber, which has a diameter greater than the external diameter of the chamber itself, creating in this way a circular flange that protrudes from the outer wall of the cyclone and blocks an air passage through an annular channel between the cylindrical circulation chamber and the co-axial tubular nozzle cylinder with larger diameter by contacting the inner wall of said nozzle cylinder, except for some minor interruptions in said flange that control the resistance to air flow of this passage, adapted to a predetermined total resistance of the circulation chamber to control the partial flow of the envelope through the annular opening between the cylinder of the co-axial nozzle and the discharge channel of the downstream circulation chamber in addition to this flange; a disintegration means for dry powder inhalers in which the number of bypass channels is between one and eight, preferably three, being substantially symmetrically distributed along the circumference of the wall of the circulation chamber, in addition to passing through the channel the medium Dosage of the inhaler and the shape of the circulation chamber has corners, preferably eight corners, with sections of the chamber wall of different lengths, in which the longer sides and the shorter adjacent sides alternate, serving the sides more long as acceleration sides along which the velocity of gain of motion particles to increase the velocity of the impact and having the shorter sides preferably obtuse angles of approximately 135 degrees with the longer sides, being suitable as impact sites ; a disintegration means for dry powder inhalers in which a tubular discharge channel has different internal diameters by its length to control the area within the circulation chamber from which the carrier particles can enter this channel and to control the discharge rate of a carrier dose with defined size distribution from the circulation chamber and more in particular, to control the residence time of the average carrier within the circulation chamber that determines the degree of fine particle detachment from the carrier and thus the dose of fine particles emitted at a certain inspiratory flow rate; a disintegration means for dry powder inhalers comprising striations or longitudinal strips in the internal tubular wall of the discharge channel or a structure formed within said channel also from wall to wall which, in the cross section, preferably has the form of a cross that divides the discharge channel into approximately four longitudinal sections, said striations or structure provide a corrective effect of the flow by eliminating the tangential flow component for particles traveling through the tubular discharge channel, thereby causing these particles to discharge substantially in the longitudinal direction instead of being thrown laterally by centrifugal action; a disintegration means for dry powder inhalers comprising two concentric annular channels between the nozzle cylinder and the discharge channel, a channel serving as an air passage through the bypass flow to the disintegration medium and the envelope flow ; the other channel serving as an internal storage site for retained carrier particles and said nozzle cylinder being movable longitudinally with respect to the discharge channel so that the carrier storage chamber is opened during inhalation or to close this chamber after inhalation is completed for use in association with concepts of disintegration media that are not designed for carrier retention itself; a disintegration means for dry powder inhalers in which the inlets of the supply channels in the circulation chamber each have substantially rectangular cross sections; a disintegration medium for dry powder inhalers with essential dimensions adapted to an inhaler system so that various embodiments of the disintegration means are easily interchangeable within the same dry powder inhaler system, to thus comprise a modular system that can be adapted to the specific requirements of the powder formulation used in the inhaler and a disintegration medium for dry powder inhalers comprising mechanical coding means that interact with the corresponding mechanical coding means in the sense of an antagonist receptor function between the system of dosing and the disintegration chamber, to allow the attachment of the disintegration media only to predetermined dosing systems or inhalers to ensure the correct associations between the disintegration medium and a predetermined medical powder formulation.

In a further aspect the invention relates to an inhaler comprising a disintegration medium as described herein.

In a further aspect a method of multiple and multi-purpose disintegration is provided for dry powder inhalers, to break drug formulations without binder, in powder, during inhalation by the patient by the inhaler after the previous activation of a single dose, in a weight range between about 2 and 25 mg, to thereby release a substantial amount of fine particles of drug for intense deposition in the lung from these formulations, which contain the drug in micronized form, preferably in the size range between 1 and 5 µm and fundamentally, but not necessarily, a carrier charge or excipient, with or about the same size distribution as the drug in so-called soft spherical granules, also referred to as soft spherical agglomerates or comprising much larger crystals that support the particles of drug as primary entities or as small groups in homogeneous distribution on its surface, joined by soft interaction forces such as van der Waals forces, in so-called adhesive, interactive or ordered mixtures, in which each carrier particle with adhered drug particles can be considered as an agglomerate as well.

In another aspect the method comprises that the agglomerates repeatedly collide with the cylindrical wall of the circulation chamber and / or each other while circulating inside the chamber, so that the drug particles are released from these agglomerates by impact and shear forces .

In another aspect, the method comprises that the separation of particles in their difference in inertia takes place by the action of drag and centrifugal forces, with the largest particles being subjected to predominant centrifugal force in the chamber and the smallest particles subjected to being released. due to the predominant drag force with the inspiratory air, as a result of which the circulation chamber acts not only as a rupture chamber for drug agglomerates but also as an air classifier, to provide the substantial reduction of drug deposition in the mouth and throat, not removing drug from the carrier crystals or disintegrating insufficiently as well as the advantage of reduced administration of the powder to the patient that minimizes the irritating oral sensation and compression in the chest.

In another aspect, the method comprises that the inhaler discharge cloud has a strong tangential flow component, which causes larger particles, such as carrier particles that are unable to reach the target area in the lungs, to be thrown laterally by centrifugal action immediately after discharge from the mouthpiece of the inhaler, thereby causing these particles to deposit in the front of the mouth in a patient instead of in the throat, thereby reducing the adverse local side effects in the throat, such as hoarseness or Candidiasis associated with the use of corticosteroids, from the drug deposition of particles that have not detached from the carrier particles and providing facilitated removal of these carrier particles by mouthwash.

The desired duration of carrier circulation in a deagglomeration chamber depends on the speed with which the drug particles can be released from the carrier crystals in this chamber. The basic air classifier described in the international patent WO 01/60341 A1 (Art. 54 (3) EPC) provides the possibility of studying this release rate. In the carrier crystals that are retained by this classifier, the residual drug (RP: carrier residue) can be analyzed after inhalation as a function of inhalation time (circulation). Carrier residues (as percentage of initial drug loading) are shown for mixtures of budesonide 0.4% with three different carrier fractions in this air classifier concept in Figure 3A for the inspiratory flow rate of 60 l / min ( equal to 9.3 kPa). The carrier fractions used were 45-63 µm, resp. 150-200 µm of Farmatosa 150 M (DMV International, The Netherlands) and 150-200 µm of Capsulac 60 (Meggle GmbH, Germany). Because a minor carrier step took place (Figure 1), all values of the remaining carrier have been extrapolated to 100% carrier withdrawal. Two different mixing times were used: 10 and 120 minutes in a Turbula mixer at 9.4 rad / s (90 rpm) (W. A. Bachofen, Switzerland). The release curves (100 minus RP) for mixtures after 10 minutes of mixing time are presented in Figure 3B.

Figure 3A shows that the rest of the carrier after 10 minutes of mixing time (open symbols) decreases most strongly in this type of classifier within the first half of a second of inhalation, towards approximately 50% of the initial charge of carrier. In the next 1.5 s, another 20 to 25% of the drug is released and the rest of the carrier is further reduced to approximately 30% (after 2 s of total inhalation time). And even after 6 seconds of inhalation, the endpoint has not yet been reached, which seems to be around 10% of the initial drug load. The results show that the differences between the different carrier fractions are not spectacular for this type of classifier (at 60 l / min).

Figure 3A also shows that an increase in mixing time decreases the rate of release of drug particles. For example, the average carrier residue (for the three carrier fractions), after a second circulation in the classifier, increases from 42% to 70% as a result of an increase in mixing time from 10 to 120 minutes. And in terms of the same degree of detachment: the effect of 0.5 s of circulation time after 10 minutes of mixing equals that of a circulation time of almost 3 seconds after 120 minutes of mixing time. These results are in accordance with the concept of total mixing introduced by Staniforth (1987), which means that there is a breakdown of cumulative drug agglomerates during mixing that results in a gradual change of the predominant cohesion between drug particles towards adhesion predominant between primary drug and carrier particles by increasing mixing time. This, together with another theory, which indicates that the removal forces during inhalation can be maintained better from larger drug agglomerates than from primary drug entities (Aulton and Clarke, 1996), explains the decrease in the rate of detachment of Fine drug particles caused by an increased mixing time for the powder.

The basic air classifier described in the international patent WO 01/60341 A1 (Art. 54 (3) EPC) is a highly effective deagglomeration principle compared to most commercialized dry powder inhalers and so are the concepts described in the German patent DE 19522416 and European patent EP 0547429. This is shown in Figure 4, which presents the fine particle fractions from these concepts and some commercialized devices: at a pressure drop of 4 kPa by these devices, collected in a cascade impactor for adhesive mixtures with different drugs and different types of carrier material. IIC represents a basic classifier of the type described in international patent WO 01/60341 A1 (Art. 54 (3) EPC) (the same as that used for Figures 3A and B), while the Novolizer is the commercialized version of the concept filed in German patent DE 19522416. The fine particle fractions obtained with CII are from mixtures with 0.4% budesonide and the types of marketed Pharmatosa carrier mentioned in the Figure. The results obtained with the Novolizer are for mixtures with 1% budesonide or 1% salbutamol sulfate and carrier materials mentioned in the legend of this figure. For marketed ips, two different formulations were also tested (see legend). All inhalation times were 3 seconds. The average fine particle fractions obtained from IIC and Novolizer are on average approximately twice as high as those obtained with ips marketed at the same pressure drop by inhalers.

Possible explanations for the differences between fine particle fractions of commercialized inhalers and air classifiers in the Cll test inhaler and the Novolizer are (a) different efficiencies in the use of the available energy of inspiration by the device and ( b) different properties for the formulations used, which contain classic lactose products for CII and the Novolizer. The amount of energy (Nm) that is available for the disintegration of the dust can be calculated by multiplying the average pressure drop by the inhaler (Nm-2) by the average volumetric air flow rate by the device (m3.s-1) and the duration of the maneuver or inhalation maneuvers. The different efficiencies in the breaking of the dust can be the result of (a) different speeds of dissipation of energy (Nm.s-1) and / or (b) different durations of the consumption or of the energy consumptions for the process of deagglomeration; the latter being the result of different residence times for the dust inside the inhaler device. It is quite obvious that for inhalers with a lower energy dissipation rate than the classifier used for Figures 3A and B, the drug release rate will also be lower. This means that a longer residence time will be necessary to obtain the same degree of fine particle shedding of the carrier crystals. If, on the other hand, the rate of energy dissipation can be increased, the residence time can be reduced, which reduces the danger of incomplete inhalation of the dose for patients unable to maintain the necessary inhalation maneuver for a certain duration.

Recent regulatory directives prescribe that the full dose can be inhaled within 2 liters. This demand limits the residence time for the dose in the deagglomeration chamber to 2 seconds at an average flow rate of 60 I / min. Considering further the need for a certain volume of air to transport the thin particles of drug released to the site of action in the airways, the release of drug particles should preferably be 'completed' in the first 1 to 1.5 s from the Beginning of the inhalation maneuver at this flow rate. These limitations for an air classifier as described in the international patent WO 01/60341 A1 (Art. 54 (3) EPC) include that only about 60 to 65% of the dose can be released from carrier materials as used in the experiments for Figures 3A and B (which is approximately 70% of the maximum release attainable from these carriers). This explains why an additional increase in the energy dissipation rate for dust breakage (Nm.s-1) has been an important aspect for this invention.

The residence time control within the circulation chamber can be obtained (a) by selecting the appropriate carrier size distribution for the adhesive powder mixture, (b) limiting the flow rate attainable by the inhaler device and (c ) vary the diameter of the discharge channel of the circulation chamber. An example of the effect of the average carrier diameter and the inspiratory flow rate in the residence time in a particular circulation chamber of the type described hereinafter, is given in Figure 5. The data has been obtained by measuring the reduction of the pressure drop through the medium, which is a consequence of the presence of particles in the chamber. Without particles, the turbulence of the air circulating inside the chamber is much greater than that of a circulation chamber loaded with particles at the same flow rate. The particles soften the flow model inside the chamber due to its much greater inertia compared to that of air. Consequently, the pressure drop across the chamber is smaller in the presence of particles. The difference can be measured as a function of inhalation time. When the reduction is reduced to zero, all particles have passed the chamber, as verified by inspection of the circulation chamber after completing the inhalation, as well as by measuring the optical concentration of the discharge cloud of the inhaler with technique of laser diffraction during inhalation.

For particles larger than 125 µm, the flow effect is almost negligible in the concept used for the preparation of Figure 5. On the other hand, the residence time for such particles in this concept is in accordance with the desired range up to 1, 5 s, as previously discussed. This is the result of the design and the default dimensions of the deagglomeration principle. The flow effect increases as the average carrier size decreases and results in a maximum value of more than 3 seconds for this particular concept at 90 l / min. For much smaller flows, the residence time is almost independent of the distribution of carrier sizes.

Better control of residence time can be obtained by varying the diameter of the discharge channel of the circulation chamber. This is shown in Figure 6 for the same concept used for the experiments in Figure 5, with two different diameters: 7 and 8 mm. The open symbols in this figure represent lactose products marketed with a relatively wide size distribution, while the closed symbols are for narrow fractions from Farmatosa 110M. The average reduction in residence time for products with an average diameter of 150 µm (or more) from the increase in the discharge channel diameter from 7 to 8 mm is almost 50% for this type of circulation chamber (at 60 l / min). These are only examples that elucidate (a) the many possibilities for controlling residence time in this type of deagglomeration chamber and (b) the time interval within which the circulation of particles within this chamber can be varied.

In addition to all the aforementioned effects, there may be a drug loading effect on the residence time of the carrier within the circulation chamber, as shown (as an example) for three different carrier materials and two different drug charges in the Figure 7, for the same concept used for Figures 5 and 6, with 7 and 8 mm discharge channels (the dose weight is approx. 14 mg). The effect of drug loading on the residence time for the carrier fraction is quite small for carriers with a relatively large diameter, but for much smaller particles, the effect can be quite substantial. The reason for the lengthening of residence time is an increase in the inertia of the circulating air within the deagglomeration chamber due to the dispersion of fine particles released into the air. As a result of this greater inertia for the aerosol compared to air without particles, the pathways of the carrier particles within the chamber can be better redirected to the original circular motion after there has been a dispersion in other directions from particle collisions. of carrier with the walls of the inhaler and / or each other. The correction efficiency is the highest for the smallest carrier crystals, having the lowest inertia themselves. The effect decreases with increasing diameter for the discharge channel: already for a concept with an 8 mm channel, the effect has decreased, even for the fraction of 63100 µm.

All previously mentioned variables that influence the residence time of the formulation within the circulation chamber can be controlled, except for the inhalation maneuver by the patient. However, by selecting the appropriate size distribution for the carrier material, the inspiratory flow effect can be minimized (Figure 5). The use of relatively large carrier materials is not problematic from the point of view of the release of fine drug particles for the type of disaggregation principle described hereinafter. This, unlike many other principles, as previously discussed. This may become clear from Figures 3 and 4. Fractions 150-200 µm in Figure 3 have the same velocity of fine particle shedding towards the same final value as the much finer fraction of 45-63 µm (at 60 l / min). The mean diameters (from the dry laser diffraction analysis) for Farmatosa 110 M and Capsulac 60 in the mixtures presented in Figure 4 are approximately 130 µm (X100 = 365 µm), respectively 190 µm (X100 = 360 to 460 µm) , depending on the lot. A larger diameter is even preferable from the viewpoint of dose reproducibility.

The residence times measured with the differential pressure drop reduction method equals the time needed to complete the carrier discharge from the circulation chamber. Because the passage of carrier particles is more or less gradual from the beginning of inhalation, the average residence time in the circulation chamber is much shorter. If the inhalation of the total dose should be within 2 liters, the total carrier step should preferably be completed within 1.5 liters so that some volume (0.5 liters) remains for the transport of fine particles to the site of action. Accordingly, the average residence time in the deagglomeration chamber is much less than 1.5 s at 60 l / min (in case of a perfectly constant discharge rate approximately 0.75 s).

From Figure 3, it can be concluded that the fine particle release after 0.75 s is only about 60% of the dose (for the highly effective basic air classifier already in international patent WO 01/60341 A1 (Art. 54 (3) EPC) and rather common carrier materials such as Farmatosa or Capsulac fractions). This includes that 40% of the dose is wasted by deposition linked with the carrier crystals in the patient's mouth and throat. This part of the dose presents the possibility of causing adverse local side effects at these sites. From 60% released from the drug dose, a certain amount is also lost by the inhaler and accumulation in the mouth, which means that less than half of the dose is available to enter the target area, provided that all The drug particles (or small agglomerates) within this part of the dose have the correct size distribution. This is an argument to further improve the concept. One possibility to increase the output of fine particles from an inhaler is to optimize the powder formulation with respect to carrier properties and mixing time (for example Figures 3A and 3B). This solution is within the scope of this invention. Another way is to increase the effectiveness of the inhaler in terms of the rate of energy dissipation for powder deagglomeration. This improvement in the effectiveness of the inhaler for adhesive mixtures is an aspect of this invention, as previously mentioned.

Within the same circulation time, the effectiveness of fine particle detachment of the carrier crystals housed within a circulation chamber can be increased by (a) increasing the speed of the carrier particles on impact, (b) increasing of the number of collisions within said circulation time and (c) optimization of the impact angle. The velocity of the particles in the impact depends not only on the velocity of the air inside the circulation chamber but also on the time available between two collisions to accelerate the particle again by the drag force. When the carrier particles collide with the wall of the inhaler, they require losing part of their moment to generate inertial forces, and more specifically, of deceleration, that act on the adhering drug particles. For the necessary acceleration time between collisions, (a) the residual velocity (in the new direction) after the collision, (b) the distance between two collision zones, (c) the air velocity inside the chamber and ( d) the mass of the particles are the most relevant. And for the residual velocity after impact to the next collision zone, the angle of impact is important as well.

The cylindrical wall of the circular chamber described in the unpublished international patent WO 01/60341 A1 (Art. 54 (3) EPC) only has two alterations of the air channels. For particles circulating in this chamber, the angle of collision with this wall of the cylindrical chamber is quite obtuse. Therefore, the loss of momentum in the impact is not extreme and as a result, the residual velocity is quite high. The particles circulate inside this chamber with high velocity when the air velocity is high and in addition to that, the number of collisions per unit of time is too high as well. The high speed and the high number of collisions compensate for the rather obtuse angle of impact. And because there is no carrier passage, the energy consumption for fine particle shedding is for the full duration of inhalation and this makes the principle of deagglomeration highly effective. By definition, the fraction of fine particles obtained with this type of principle is highly dependent on the flow rate.

For the concept described in German patent DE 19522416, the angle of impact against residual sections of the inner wall of the circulation chamber is 45 degrees, which is optimal in the balance between impact angle and residual particle velocity, but the distance Between the sections is quite small. In addition to that, the number of air bypass channels to the circulation chamber is high, which reduces the air velocity within these channels. Therefore, the acceleration of the carrier particles in the new direction after collision is not maximum. The concept is very appropriate for the disintegration of soft spherical granules, as previously described, but for adhesive mixtures, the best possible result cannot be obtained.

For the newly developed concept for adhesive mixtures described hereinafter (technical description), the basic shape of the circulation chamber is an octagon with eight angles of 45 degrees each. However, unlike the German patent DE 19522416, not all sides of the octagon have the same length: four longer sides alternate with four shorter sides. The latter includes the impact sites for the carrier particles. Also unlike this previously described concept, the number of bypass channels is only three. Therefore, the air velocity within these channels is much higher at the same inspiratory flow rate through the circulation chamber. Accordingly, the drag force for the acceleration of the carrier particles within the chamber is much greater. The particles accelerate along the longer sides of the octagon and impact on the adjacent shorter side. Both the greater initial drag force and the longer trajectories for particle acceleration contribute to a higher impact speed.

On average, the particles bounce against the impact side at approximately the same angle as the impact angle and after deviation, they are immediately accelerated to the next impact side. However, some particle dispersion takes place in other directions, due to the irregular shape of the carrier crystals. As a result of this dispersion at a higher speed (compared to the impact velocity of carrier particles at the same flow rate in the concept described in German patent DE 19522416), the speed of passage through the discharge channel is greater. Although this download speed can be controlled quite well by selecting the appropriate carrier size distribution and diameter for the discharge channel, as previously discussed. The highest carrier circulation speed (of all concepts) in the international patent WO 01/60341 A1 (Art. 54 (3) EPC), does not result in the highest carrier discharge rate of this classifier concept of basic air, due to the obtuse angle of impact and the extension of the discharge tube that protrudes into the circulation chamber. Most of the particles in this concept do not disperse in the direction of the discharge channel and the few that do, cannot (with a few exceptions) enter this channel due to their extension protruding from the upper wall of the classifier.

The average velocity of the particles with which the particles circulate within the newly developed concept is between those concepts described in German patent DE 19522416 and the international patent WO 01/60341 A1 (Art. 54 (3) EPC) at the same inspiratory flow rate: The reason for this is that the distance between the impact sites in this new concept is shorter than the distance required to accelerate the particles towards the air velocity inside the chamber. This has the advantage that the fine particle fraction (FPF) depends less on the inspiratory flow rate than on the international patent WO 01/60341 A1 (Art. 54 (3) EPC).

As for the concept with almost complete carrier retention (international patent WO 01/60341 A1 (Art. 54 (3) EPC)), the FPF depends on the residence time in the circulation chamber of the newly developed concept for adhesive mixtures as well. This is shown in Figure 8 for two different designs of this new concept (open and closed symbols) compared to the FPF of the disaggregation means described in German patent DE 19522416 (asterisks), using a mixture with Capsulac 60 and budesonide at 2%. The closed symbols represent the FPF of the most effective design of this concept. The increased efficiency has reduced the circulation time necessary for the release of approximately 40% of the drug particles from the carrier crystals from two to less than one second.

The figure shows the same type of correlation between residence time and FPF as in Figure 3B, but there are some relevant differences. For the basic air classifier in Figure 3B, no envelope flow was used. Consequently, the complete inspiratory air flow was conducted through the deagglomeration chamber during the experiments. For the newly developed concept for adhesive mixtures with controlled carrier passage in Figure 8, approximately 1/3 of the total flow rate has been used as a wrapper flow to limit the air flow resistance of the concept to a value conforming to the patient. The curves in Figure 3B represent the percentages of drug that have come off the carrier crystals, while the curves in Figure 8 are for the fraction of fine particles collected in a cascade impactor. Therefore, the difference between both types of curves is the adhesion of the drug in the inhaler device and the inlet tube to the impactor. There may also be some losses of the finer drug particle fractions from passing through the final impactor stage. Finally, the residence time in Figure 3B is for the almost complete bearer fraction, while the residence time in Figure 8 is the time necessary for complete carrier discharge. The average duration of bearer circulation in the newly developed concept is therefore approximately half of the residence time presented.

Taking into account all these differences, it can be concluded from the comparison of Figures 3B and 8, that the difference in effectiveness between the newly developed concept and the concept presented in the international patent WO 01/60341 A1 (Art. 54 (3) EPC) is quite substantial. The fraction obtained from fine particles for the concept optimized in Figure 8 is almost 45% of the dose after a residence time of 1 second, which means that the average circulation time was only about 0.5 s. This is approximately the same percentage as that found for the release of drug particles in Figure 3B after 0.5 s. Thus, after correction for (a) the losses in FPF due to adhesion in the inhaler and inlet tube and (b) the difference in flow through the deagglomeration chamber (reduced to one third for the newly developed concept as a result of the application of the envelope flow), the release of the drug in half a second is much greater in this new concept. By reducing the envelope flow, an additional increase in efficiency is possible, but the resulting increase in resistance to air flow may make the inhaler use less conforming to the patient.

The reduction of residence time to a period of less than 1 to 1.5 seconds or even less for flows greater than 60 l / min, seems more or less mandatory considering the recent regulatory directives, which require that the full dose can be inhaled in 2 liters. As shown in Figure 8, this practically limits the fine particle fraction to approximately 40 to 50% of the nominal dose for adhesive mixtures, even when inhaled from a highly effective disintegration medium. Especially for the interval up to one second, the FPF decreases greatly as the circulation time decreases. Thus, it is necessary to fine tune the residence time to obtain the best possible therapeutic effect of an inhalation dose. Within the same range of circulation times (0 to 1 s), the properties of the carrier material in adhesive mixtures, which are relevant for the release of drug particles, are the most critical, too. Therefore, a good breakdown of the dust up to a residence time of one second is difficult to achieve and this should be a serious argument for the reconsideration of the aforementioned demand. Description of preferred embodiments of the invention

The description of the newly developed concept will be based on attached drawings.

The modular design of the deagglomeration means is another aspect of the invention. It allows the exchange of different concepts (for example, basic air classifier replaced by the principle of deagglomeration optimized for adhesive mixtures) within the same inhaler device and / or the use of the concepts in different inhalers. The choice of concept depends on (a) the specific application or

(b) the type of formulation.

In addition to the modular design with different concepts for the deagglomeration chamber, various embodiments and variations are useful and preferred and include the use of longitudinal flow tilbes within the discharge channel of the circulation chamber that eliminate the tangential flow component (at cost of increased drug accumulation in this channel) and the use of a special nozzle for the inclusion of large carrier particles that are thrown in a radial direction by centrifugal action immediately after the discharge of the nozzle. This reduces the irritated sensation of the mouth and candidiasis from carrier deposition in the mouth. The nozzle can be designed as a double (co-axial) cylinder so that an annular chamber is created between the two cylinders for storage of retained carrier particles. Before inhalation, the outer nozzle is moved against the inner cylinder (by rotation, using a screw thread or pulling) in the longitudinal direction to create a passage for the carrier particles. After inhalation, the annular chamber closes again. Brief description of the drawings function of the inhalation time at 60 l / min for an air classifier similar to the concept described in the international patent WO 01/60341 A1 (Art. 54 (3) EPC). Continuous lines with open symbols represent mixtures after 10 minutes of mixing time; closed symbols with dashed lines are for mixtures after mixing time of 120 minutes. Carrier materials are sieve fractions of 45-63 µm and 150-200 µm from Farmatosa 150 M and 150-200 µm size fraction of Capsulac 60. The dose weight is 25 mg;

Figure 1

It is a diagram showing the effectiveness of carrier elimination of

a

sorter from air Similary to the concept described in the patent

International WO 01/60341 A1 (Art. 54 (3) EPC)

how function of

average carrier diameter for narrow size fractions of

different types of crystalline alpha-lactose monohydrate at 30 and 40 l / min.

The dose weight is 25 mg;

Figure 2

It is a diagram showing the limit diameter of an air classifier

similar to the concept described in international patent WO 01/60341 A1

(Art. 54 (3) EPC) as a function of the flow through the sulfate classifier

of colistin with a relatively wide size distribution between

0.7 and 87 µm when

be measure with a laser diffraction apparatus

(Sympatec,

HELOS compact, model KA with lens from 100 mm)

after dispersion RODOS. Limit values equal to values

of X100

laser diffraction analysis of the cloud spray

inhaler

from test United to a adapter from  inhaler special

(RuG test model);

Figure 3A

It is a diagram showing the rest of the carrier, extrapolated to withdrawal

100% for adhesive mixtures

with 0.4% budesonide how

Figure 3B is a diagram showing the drug release rate for mixtures with budesonide 0.4% at 60 l / min for an air classifier similar to the concept described in international patent WO 01/60341 A1 (Art. 54 ( 3) EPC). The curves have been calculated as 100 minus the values in Figure 3A;

Figure 4 is a diagram showing fine particle fractions for some commercialized ips and two different concepts of the invention, all with adhesive mixtures, obtained at 4 kPa by the inhalers. Glaxo Diskus and Diskhaler both with Flixotide and Serevent formulations; ISF inhaler with budesonide (Cyclocaps, Pharbita) and Foradil (Ciba Geigy). CII air classifier, similar to the concept in the international patent WO 01/60341 A1 (Art. 54 (3) EPC), with mixtures of budesonide 0.4% for the indicated carriers of Farmatosa; Novolizer (with the concept of German patent DE 19522416) with mixtures of budesonide at 1% resp. 1% salbutamol in Capsulac 60 (left beams per drug) and a mixture of Capsulac 60 and Farmatosa 450 M 5% (right beams per drug);

Figure 5 is a diagram showing the residence times of narrow sieve fractions from Farmatosa 110M as a function of average fraction diameter at three different flow rates in the newly developed concept for adhesive mixtures with 8 mm discharge channel. The dose weight is 10 to 11 mg;

Figure 6 is a diagram showing the residence times of different types of carrier material in the newly developed concept for adhesive mixtures, for two different discharge channels at 60 l / min. The closed symbols are narrow fractions of sieves from Farmatosa 110M; The open symbols are for lactose products marketed with different average diameters. The dose weight is approx. 11 mg;

Figures 7A and B are diagrams showing residence times of mixtures

adhesives with two different drug fillers (budesonide 0.4 and

4.0%), compared to unmixed carrier materials,

for the newly developed concept with 7 (Figure 7A), respectively

8 mm discharge channel (Figure 7B) at 60 l / min. The dose weight

is approx. 14 mg The carrier fractions come from Farmatosa

110 M (63-100 and 150-200 µm) and Capsulac 60 (150-200 µm);

Figure 8

it is a diagram showing the fraction of fine particles as

function of residence time in different concepts of

newly developed disaggregation principles for mixtures

adhesive measures with a four-phase Lenz Labor impactor

Fisons type at approx. 4 kPa per devices. Mix: Capsulac 60 with

2% budesonide. The residence times for Figures 5, 6, 7 and

8 have been obtained from the suppression-dP measurement;

Figure 9

it is an exploded perspective view of the concept of

basic air sorter of the disintegration medium with retention of

carrier;

Figure 9A

It is a cross-sectional view of the basic air classifier concept

assembly of figure 9;

Figure 10

It is a diagram showing the main flow components of the

streamlines of air paths and particles within

the circulation chamber of the basic air classifier in relation to

the forces acting on these particles;

Figure 11

it is an exploded perspective view of the concept with

air barrier inside the circulation chamber that prevents adhesion

substantial fine particles in the inner wall of the chamber,

especially during the rupture of soft spherical granules;

Figure 12

it is an exploded view of the inventive concept with sides of

separate acceleration and impact sides and a release speed

controlled for carrier crystals and

Figures 13A to E are exploded views of some different modifications of the upper plate of the circulation chamber with a flow channel.

download connected to it, for the concepts shown in the

Figures 11 and 12.

The invention explained in general lines above and all its specific features, as elucidated in part in Figures 1 to 8, will become apparent from the technical description given from now on, which will have to be read in relation especially to the drawings in figures 9 to 13.

It will be understood by one skilled in the art that Figures 9 to 13 show possible embodiments as an example and that these can be modified in many different ways without departing from the scope of the invention as discussed in general lines and further defined in the claims.

By all the drawings, the same or similar elements are designated with the same reference sign for ease of understanding of the invention.

Figure 9 shows the basic air classifier connected to an inhaler body 1 without representing details of the dosing mechanism from which the amount of dust, which represents a single dose, is carried by the inspiratory air flow through channel 2 of dust The circulation chamber 3 of the air classifier is cylindrical, being a height smaller than its diameter and a rounding 4 of little importance in the position of the transition from the cylindrical wall 5 to the wall 6 of the bottom of the chamber 3. The particle-laden air through channel 2 of the powder is forced to change its flow direction after reaching the upper plate 8 of the circulation chamber 3 by a 90 degree turn to the final section 2A of the channel 2 of the powder, which is it approaches the circulation chamber as a tangent to its cylindrical wall 5. On the opposite side of the circulation chamber 3 is the inlet for the bypass flow to this chamber, which is a second part of the inspiratory flow, which is the final section 9A of a bypass flow channel 9. This final section 9A of the bypass flow channel 9 is also constructed as a tangent to the cylindrical wall 5 of the circulation chamber 3 to support the basically circular air flow within this chamber 3, as shown in Figure 10. The depths of the final sections 2A and 9A of the powder flow channel 2 and the bypass channel 9, which have rectangular cross sections, are approximately half the depth of the circulation chamber 3 of the classifier. The bypass flow channel 9 upstream of its final section 9A has been created by reducing the thickness of the section 10A of the outer cylindrical wall of the circulation chamber 3, adjacent to the section 9A of the channel, for the same diameter as for section 10B thinner and at the same height as the depth of the final section of channel 9A of the bypass flow.

The cylindrical wall 10 of the circulation chamber 3 has two thinner sections 10B and two thicker sections 10A through which the air passages 2 and 9 have been constructed, the four sections extending equally from the circumference of this wall, corresponding to angles of approximately 90 degrees. In the upper plate 7 of the central inhaler box 1, in the positions corresponding to the thinner sections of the wall 10, there are openings 11 that serve as steps for the partial bypass flow and the envelope flow. The air that goes through these steps 11 enters an annular chamber 12, as shown in Figure 9A, between the cylinder 13 of the tubular nozzle and the cylindrical wall 10 of the circulation chamber 3. As a result of the local differences in the thickness for the cylindrical wall 10 of the circulation chamber 3, the annular chamber 12 has different widths. Figures 9 and 9A do not show the inlet opening for the inspiratory flow and the division of this flow into (a) a partial flow through the dose measurement or dose delivery section of the inhaler before it enters the circulation chamber through the dust channel 2 and (b) another partial flow entering the annular chamber 12 through the openings 11. These aspects are part of the design of the inhaler and are not relevant to the invention.

In Fig. 9, the upper plate 8 of the circulation chamber 3 is a separate part that is pressed adjusted to the cylinder 13 of the nozzle by means of a soft lock in this cylinder. The cylinder 13 of the mouthpiece is placed on the cylindrical wall 10 of the circulation chamber 3 and is fixed to the case 1 of the inhaler by a bayonet closure of which the projections 15, attached to the cylinder 13 of the mouthpiece, fixed in the gaps 15A slightly sharp below the raised edge 16 locally interrupted adjacent to the outer wall 10 of the circulation chamber 3. In the final position of the projections 15 in the sharp slits 15A, the upper plate 8 is pressed firmly against the edge 17 of the cylindrical wall 10 of the circulation chamber 3. Figure 13E shows that this upper plate 8 can also be an integral part of the circulation chamber 3; alternatively (not shown), it can be an integral part of the nozzle cylinder 13 itself. The upper plate 8 as shown in Figures 9 and 9A, is basically circular but has two different diameters 14A and 14B for different sections of this plate, corresponding to the different diameters 10A and 10B for the cylindrical wall 10 of the chamber 3 of circulation when the nozzle cylinder 13 detaches in position. The space 18 in Figure 9A between the inner wall of the cylinder 13 of the nozzle and the upper plate 8 of the circulation chamber 3, in the positions in which the upper plate has a reduced diameter, serves as a passage for the flow of envelope , which is a third of the total inspiratory flow. The total cross-sectional area of the two quarters of the basically annular slit between the inner wall of the channel 13 of the nozzle and the upper plate 8 of the circulation chamber contributes to the air flow resistance of the total passage for the flow of envelope.

The upper plate 8 of the circulation chamber 3 has a tubular passage 19 for the release of the aerosol cloud from said chamber 3. The discharge channel 19 shares its axis with the circulation chamber 3 but has a smaller diameter than the chamber 3. A lower part 19A of the channel 19 protrudes into the circulation chamber 3 for a distance that is slightly longer than half the depth of the chamber 3. The other part 19B of the channel 19 protrudes through an upper plate 20 of the cylinder 13 of the nozzle. The outer diameter of the discharge channel 19 is slightly smaller than the diameter of the circular hole 28 (Figure 11) in the upper plate 20, thus creating a narrow annular passage 21 for the envelope flow. This narrow passage 21 also contributes to the resistance to total air flow for the envelope flow. The mentioned resistances for the envelope flow are carefully balanced with respect to the airflow resistance of the circulation chamber 3 to control the partial flows by the inhaler. The annular slit 21 between the discharge channel 19 and the upper plate 20 of the nozzle cylinder 13 has no interruptions, to create a non-rotated co-axial wrap of air without particles around the aerosol cloud of the discharge channel 19.

The working principle of the basic air classifier concept is explained in Figure 10. Figure 10A shows relevant components of the air stream lines within this chamber, while Figure 10B is a schematic representation of the forces acting on particles of different sizes and in different regions of circulation. The main component of the current lines along the periphery of the circulation chamber 3 in Figure 10A is in a tangential direction, while closer to the discharge channel 19, which begins in the center of the chamber 3, the Flow components in the radial and longitudinal directions increase as air enters this channel. The agglomerates with relatively large inertia, which enter the circulation chamber 3 along its periphery, begin a basically circular path along its internal wall 5 where the centrifugal force (FC) is dominant (Figure 10B). Even after the collision with the inner wall 5 of the circulation chamber 3, as a result of which the particles can bounce against this wall and approach the discharge channel 19 in the center of this chamber 3, the larger agglomerates will return to the original circular route due to its high momentum (mV), together with the acceleration of drag force (FD). However, the fine particles that emerge from these agglomerates, present a much lower moment, while the drag force is relatively high compared to the centrifugal force, especially in regions of circulation at a certain distance from the wall 5 of the chamber 3 circulation. These particles can follow the streamlines of the air and are discharged from the circulation chamber 3, while larger agglomerates are retained within this chamber 3 by the action of the centrifugal force.

The basic air classifier is particularly suitable for the disintegration of adhesive mixtures, in which the large carrier crystals act as cleaning crystals that keep the inner cylindrical wall 5 of the circulation chamber 3 free of adhered fine drug particles. Without the presence of these cleaning crystals, the accumulation of fine particles within this chamber 3 is substantial, as in similar swirl, whirlpool or cyclone chambers applied in other dry powder inhalers.

In another embodiment of the invention, as shown in Figure 11, the principle is particularly suitable for the disintegration of soft spherical granules or adhesive mixtures for which larger particles such as carrier crystals are not retained but are gradually released. of the circulation chamber 3. This concept is different from the concept in Figure 9 with respect to the shape and depth of the circulation chamber 3, the number and shape of the channels for the bypass flow 9, the shape of the dust channel 2, the plate 8 upper of the circulation chamber and the discharge channel 19 for the circulation chamber attached thereto, as well as the passage of air towards the bypass channels 9. In addition to that, some construction differences are shown between the concepts of Figures 9 and 11 that are not essential to the scope of the invention.

The concept in Figure 11 has seven identical channels 9 for the bypass flow, of which each has a generally rectangular shape in cross-section and approximately the same depth as the circulation chamber. The channels 9 provide the circulation chamber 3 in top view largely in the form of an octagon with eight identical open angles of 135 degrees between the remaining sections 22 of the inner wall 5 of the circulation chamber 3. The powder flow channel 2 is the same as for the concept in Figure 9, except the depth of the final section 2A of the channel 9 which is the same as that of the circulation chamber 3. Air flows from the bypass channels 9 and dust 2 rubs through these remaining sections 22, which are the impact areas for the largest agglomerates. Only larger particles can pass through these flows as a result of their high momentum. Fine particles with much smaller inertia, take the course by bypass flows, which create a so-called internal air barrier between these particles and the remaining sections of the wall. Therefore, the fine particles cannot hit these sections 22. Therefore, the adhesion of the fine particles on the impact zones of the sections 22 is very low, compared to the adhesion on the inner wall 5 of the chamber 3 of circulation for the concept shown in figure 9, even from the disintegration of spherical granules. The circulation chamber 3 of this concept does not present a rounding between the remaining sections 22 of its inner wall and its bottom 6.

The discharge channel 19 in the center of the upper plate 8 for the circulation chamber 3 for the concept in Figure 11 does not present a projection in this circulation chamber 3. The channel 19 has an inner wall 23 with a constant diameter, but an outer wall 24 with a diameter that increases exponentially from the upper edge 19C towards the upper plate 8 of the circulation chamber 3. This is to direct the flow of envelope through the annular channel 21 between the discharge channel 19 and the upper plate 20 of the cylinder 13 of the cavity nozzle 25 (as shown in Figure 9) between both upper plates 20 and 8 as smoothly as possible. Due to the absence of a projection part 19A of the discharge channel 19 of the upper plate 8 of the circulation chamber 3 in this chamber 3, the passage to the discharge channel 19 for larger particles that bounce against the remaining sections 22 of the cylindrical wall of the circulation chamber 3 after impact, is much more extensive. This increases the area from which large particles can enter the discharge channel 19. In addition to that, the angles with which the particles bounce against the impact zones 22 are less obtuse than those of the basic air classifier with a circular internal wall 5 (concept in Figure 9). As a consequence, the trajectories of the particles within the circulation chamber 3 of the concept in Figure 11 more frequently cross the area from which the particles can enter the discharge channel 19. Therefore, large particles are gradually released from the circulation chamber 3 and there is no carrier retention for this particular concept of the principle of disintegration.

The upper plate 8 of the circulation chamber 3 for the concept in Figure 11 has the same diameter for its full circumference. The envelope flow supply from the annular chamber 12 (Figure 9A) to the cavity 25 (Figure 9) between this upper plate 3 and the upper plate 20 of the nozzle cylinder 13 is by a series of notches 26 along the circumference 14 of the upper plate 8, which has carefully controlled shape and dimensions. For the concept in Figure 11, the number of notches 26 is six and they are distributed symmetrically by the circumference 14 of the upper plate 8 with angles of 60 degrees between them. The total airflow resistance of these notches 26 together with the airflow resistance of the annular channel 21 between the discharge channel 19 and upper plate 20 of the nozzle cylinder 13 determines the velocity of the envelope flow with respect to the partial deviation and dust flow through the inhaler.

The shape of the nozzle cylinder 13, which is circular with a diameter that gradually decreases from the bottom edge 29 to the top edge 27 for the concept in Figure 9, is not particularly relevant to the scope of the invention, but rather by changing from circular to oval in the same direction for the concept shown in Figure 11. The upper edge 27 can be raised in relation to the upper plate 20 of the nozzle cylinder 13.

The concept of the principle of disintegration according to the invention is represented in Figure 12. For this concept, the shape of the circulation chamber 3 is basically that of an octagon, but the eight sides of the octagon have two different lengths. Four longer sides 32 of preferably generally identical length alternate with four smaller sides 22 of preferably generally identical length. The longer sides 32 serve as acceleration zones for agglomerates that have relatively high inertia and require a certain distance by which they can be dragged by the air stream to increase speed, while the smaller sides 22 serve as areas of impact for these particles. The number of channels 9 for the bypass flow has been reduced to three, compared to the concept depicted in Figure 11. The cross-section of these channels is generally rectangular and the cross-sectional area along the channel 9 is slightly larger than that of the bypass channels 9 in the concept shown in Figure 11. Despite this, the sum of the cross-sectional areas for all channels 9 is less than that of the concept in Figure 11. As a result, the Air velocity within channels 9 for the bypass flow is the highest for the concept in Figure 12, while the total air flow resistance of this step for bypass flow is slightly higher as well.

As for the concept represented in Figure 11, the discharge channel 19 has no part 19A protruding from the circulation chamber 3. The internal diameter of the channel 19 is adapted to the desired residence time of carrier crystals within the circulation chamber 3. By varying this diameter, the region within the chamber 3, from which the carrier particles can enter the channel 19, can be controlled, as shown in Figure 8, where similar symbols represent the residence times of the same concept without However, with different diameters for the discharge channel 19. The upper plates 8 attached to the discharge channels 19 with different diameters, can be the same from another point of view, as shown in Figure 13B1-B3, except the number of notches 26 for the envelope flow (optionally, but not necessarily). They have coupled nozzle cylinders 13 of which the circular holes 28 in their upper plates 20 conform to the outer diameters of the channel 19 such that the cross-sectional areas for sheath flow through the annular channels 21 between the walls 30 inside the circular holes 28 and the outer walls 24 of the discharge channels 19 are approximately the same. The number of notches 26 for the envelope flow along the circumference 14 of the upper plate 8 for the circulation chamber 3 can be varied (Figure 13B1) to fine tune the air flow resistance of the total flow passage wrap, in relation to the resistance to air flow of the circulation chamber 3.

In another embodiment of the upper plate 8 for the circulation chamber 3, the discharge channel 19 has two different sections, with an upper section 23A having a constant internal diameter and a lower section 23B with an increasing diameter towards the circulation chamber (Figure 13B4). The transition is approximately at the midpoint of channel 19. The lower part of this channel 19 has the shape of a trunk. For control of the residence time of the wearer within the circulation chamber 3, the width of the base of this trunk can be varied. This has the advantage that adaptation of the nozzle channel 13 is not necessary and that different discharge channels 19 can be used, providing different residence times, together with the same nozzle cylinder 13.

Figure 13C shows an upper plate 8 for the circulation chamber 3 with discharge channels 19 with longitudinal grooves 31 at equal distances from each other on their internal walls. Said longitudinal streaks 31, which extend along the total length of the discharge channel 19 and protrude from its inner wall 23 to the

5 channel 19 for a distance that is smaller than the internal diameter of the channel 19, can transform the movement of the particles within this channel 19 substantially from helical to longitudinal direction. This reduces the deposition in the front of the mouth from centrifugal rotation of particles with relatively large inertia, such as carrier crystals, which will still carry part of the drug dose in

10 its surface after leaving the circulation chamber 3. This reduces the buccal sensation, but increases the deposition of the throat. For most applications, a design without these striations 31 will therefore be preferable. The grooves 31 can protrude so far in the discharge channel 19, that they reach each other and comprise a solid structure 34 that, as seen from above, has the shape of a

15 cross. (fig 13D). Finally, an ascending design is shown in Figure 13 (E) in which the upper plate 8 of the circulation chamber 3 is an integral part of this chamber. Said construction has the advantage that the transition from the longitudinal part of the dust channel 2 to the final section 2A, which is a tangent to the chamber 3 of

The circulation and in which the direction of the flow is perpendicular to that of section 2, can be constructed with a certain rounding 33. Said rounding provides a substantial reduction in the accumulation of dust in this transition zone of the flow.

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Claims (14)

1. A disintegration means for dry powder inhalers, comprising a substantially cylindrical air circulation chamber (3), being a height less than its diameter, the chamber having a cylindrical wall and at least two channels (2, 9) of air supply entering the chamber (3) as tangents to the cylindrical wall (5) on generally opposite sides of this wall (5), suitable for creating a circular air flow model within the chamber (3) or the two air channels (2, 9) having different air inlets or alternatively sharing the same inlet that is divided, so that it has a step (2) to pass through the dose measurement or dose supply region of the inhaler to allow the amount of powder from a single dose to be drawn into the air circulation chamber (3) that flows through this step (2) and to serve the other step as a channel (9) bypass towards the circulation chamber (3) suitable to accelerate the particles and create a more symmetrical flow model within said chamber (3), characterized in that the number of bypass channels (9) is between one and eight, preferably three, the channels being preferably substantially symmetrically distributed along the circumference of the wall (5, 10) of the circulation chamber (3) [in addition to the channel (2) running through the dose medium � Of the inhaler] and the shape of the circulation chamber (3) has corners, preferably it has eight corners, the chamber wall (5) having sides of different lengths, in which the longer sides (32) and the adjacent smaller sides (22) alternate, the longer sides (32) serving as acceleration sides together with speed of motion particle gain to increase the speed of impact, the smaller sides being suitable as impact sites �

2.

A disintegration means for dry powder inhalers according to claim 1, characterized by a tubular discharge channel (19) with approximately the same longitudinal axis as the circulation chamber (3) but a much smaller diameter and an extension (19A) of this channel (19) protruding said chamber (3) by a length that is less than the total height of the circulation chamber (3).

3.

A disintegration means for dry powder inhalers according to any preceding claim, characterized by a third air passage (12, 18, 21, 25, 26) in addition to the two air supply channels (2, 9) previously mentioned for circulation chamber (3) or with a separate input channel or as a

branching of the cyclone bypass channel (9), through which the air flows, which is part of the total inspiratory flow, is controllable by means of a constriction (21, 26) of air flow and whose passage (12, 18, 21, 25, 26) ends in an annular opening (21) between the discharge channel (19) of the circulation chamber (3) and a coaxial nozzle cylinder (13) with internal diameter larger than the channel (19) discharge, to control the total airflow resistance of the inhaler device and to create a clean air wrap around the aerosol cloud that reduces the deposition in the mouth of drug particles released from spherical granules that is a consequence of flows of return that take place in the mouth during inhalation by an inhaler with a tubular nozzle cylinder typically with a diameter less than the height or width of the oral cavity.

Four.

A disintegration means for dry powder inhalers according to any preceding claim, characterized by more than one, preferably seven, air supply channels (9) for the bypass flow, all being substantially symmetrically distributed along the circumference of the wall (5) ) cylindrical of the circulation chamber (3), in addition to the channel (2) that crosses a dose compartment of the inhaler, when used, providing a so-called air barrier between the circulating particles and the inner wall of the chamber created by flows of air through the bypass channels (9) that are closely adjacent to each other, as well as a reduced surface of said wall (5), further providing a fine particle adhesion strongly reduced to said wall (5), especially for association with soft spherical granules;

5.

A disintegration means for dry powder inhalers according to claim 4, wherein obtuse angles of approximately 135 degrees are provided between the remaining sides (22) of the cylindrical wall (5) by the air supply channels (9) which they enter the circulation chamber (3), which in their use provide an increase in the angle of impact and cause the particles to bounce against these sides (22) of the chamber wall (3) towards the center of this chamber (3 ) by a greater distance that allows the carrier particles to approach or cross the central area of the circulation chamber (3) from which they can enter the discharge channel (19), which results in a gradual release of particles of carrier from the circulation chamber (3) through said discharge channel (19).

6.

A disintegration means for dry powder inhalers according to any preceding claim, characterized by an upper end of the circulation chamber (3) on its side of the discharge channel (19) forming a top plate (8) of

said chamber (3), which has a diameter greater than the external diameter of the chamber itself (3), thereby creating a circular flange extending from the wall

(10)

external of the cyclone and blocks an air passage through an annular channel (12) between the cylindrical circulation chamber (3) and the cylinder (13) of the co-axial tubular nozzle with larger diameter making contact with the inner wall of said cylinder (13) of the nozzle, except for some minor interruptions in said flange (18, 26) that controls the resistance to air flow of this passage, adapted to a predetermined total resistance of the circulation chamber (3) to control the flow of partial wrapping by the annular opening (21) between the cylinder (13) of the co-axial nozzle and channel

(19)

of discharge of the chamber (3) of circulation downstream in addition to this flange.

7.

A disintegration medium for dry powder inhalers according to any preceding claim, characterized in that the shorter sides (22) with preferably obtuse angles of approximately 135 degrees with the longer sides (32).

8.

A disintegration means for dry powder inhalers according to any preceding claim, characterized in that a tubular discharge channel (19) has different internal diameters for its length to control the area within the circulation chamber (3) from which they can enter carrier particles in this channel (19) and to control the discharge rate of a carrier dose with defined size distribution from the circulation chamber (3), and more particularly to control the average residence time of the carrier within the circulation chamber (3) that determines the degree of fine particle detachment from the carrier and thus, the dose of fine particles emitted at a certain inspiratory flow rate.

9.

A disintegration means for dry powder inhalers according to any preceding claim, characterized by longitudinal grooves (31) or strips in the internal tubular wall of the discharge channel (19) or a structure (34) formed within said channel (19) likewise from wall to wall which, in the cross section, preferably has the shape of a cross that divides the discharge channel (19) into approximately four longitudinal sections, said grooves (31) or structure

(34) provide a corrective effect of the flow by eliminating the tangential flow component for particles traveling through the tubular discharge channel (19), thereby causing these particles to discharge substantially in the longitudinal direction instead of being thrown laterally by centrifugal action.

10.

A disintegration means for dry powder inhalers according to any preceding claim, characterized by two concentric annular channels between the nozzle cylinder (13) and the discharge channel (19), a channel (12) serving as an air passage for the bypass flow to the disintegration medium and the envelope flow; the other channel serving as an internal storage site for retained carrier particles and said cylinder (13) being movable from the nozzle in a longitudinal direction with respect to the discharge channel so that the carrier storage chamber is opened during inhalation or for close this chamber after inhalation has been completed for use in association with concepts of disintegration media that are not designed for carrier retention.

eleven.

A disintegration means for dry powder inhalers according to any preceding claim, characterized in that the inlets of the supply channels (2, 9) to the circulation chamber (3) each have substantially rectangular cross sections.

12.

A disintegration medium for dry powder inhalers according to any preceding claim, characterized by essential dimensions adapted to an inhaler system so that various embodiments of the disintegration means are easily interchangeable within the same dry powder inhaler system, to thereby comprise a system modular that can be adapted to the specific requirements of the powder formulation used in the inhaler.

13.

A disintegration medium for dry powder inhalers according to any preceding claim, characterized by mechanical coding means that interact with the corresponding mechanical coding means in the sense of a receptor antagonist function between the dosing system and the disintegration chamber, for allow the attachment of the disintegration media only for predetermined dosing systems or inhalers to ensure correct combinations between the disintegration media and a predetermined medical powder formulation.

14.

An inhaler characterized by a disintegration means according to any preceding claim.